WO2021234081A1

WO2021234081A1 - Chemical process

Info

Publication number: WO2021234081A1
Application number: PCT/EP2021/063450
Authority: WO
Inventors: Edouard Godineau; Simon GRASSL; Paul Knochel; Alexander KREMSMAIR
Original assignee: Syngenta Crop Protection Ag
Priority date: 2020-05-21
Filing date: 2021-05-20
Publication date: 2021-11-25
Also published as: GB202007595D0

Abstract

The present invention provides, inter alia, a process for producing a compound of formula (I) wherein the substituents are as defined in claim 1. The present invention further provides intermediate compounds utilised in said process, and methods for producing said intermediate compounds.

Description

CHEMICAL PROCESS The present invention relates to a novel process for the synthesis of herbicidal pyridazine compounds. Such compounds are known, for example, from WO 2019/034757 and processes for making such compounds or intermediates thereof are also known. Such compounds are typically produced via an alkylation of a pyridazine intermediate. The alkylation of pyridazine intermediates is known (see for example WO 2019/034757), however, such a process has a number of drawbacks. Firstly, this approach often leads to a non-selective alkylation on either pyridazine nitrogen atom and secondly, an additional complex purification step is required to obtain the desired product. Thus, such an approach is not ideal for large scale production and therefore a new, more efficient synthesis method is desired to avoid the generation of undesirable by-products. Surprisingly, we have now found that the generation of a 6-membered heteroaryl organometallic can be coupled with an already alkylated pyridazine avoiding the need for such a selective alkylation. Furthermore, we have also surprisingly found that the use of a metal amide base and a suitable additive can afford a mild, practical and regioselective deprotonation of the 6-membered heteroaryl allowing for the reaction with the required electrophile. If necessary, this can then further be converted to the desired herbicidal pyridazine compounds. Such a process is more convergent, which may be more cost effective and may produce less waste products. Thus, according to the present invention there is provided a process for the preparation of a compound of formula (I) or an agronomically acceptable salt or zwitterionic species thereof:

wherein A is a 6-membered heteroaryl selected from the group consisting of formula A-I to A-VII below

wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I), p is 0, 1 or 2; and R¹ is hydrogen or methyl; R² is hydrogen or methyl; Q is (CR^1aR^2b)m; m is 0, 1 or 2; each R^1a and R^2b are independently selected from the group consisting of hydrogen, methyl, –OH and –NH2; Z is selected from the group consisting of –CN, -CH₂OR³, -CH(OR⁴)(OR^4a), -C(OR⁴)(OR^4a)(OR^4b), – C(O)OR¹⁰, -C(O)NR⁶R⁷ and -S(O)₂OR¹⁰; or Z is selected from the group consisting of a group of formula Za, Zb, Zc, Zd, Ze and Zf below

wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I); and R³ is hydrogen or -C(O)OR^10a; each R⁴, R^4a and R^4b are independently selected from C₁-C₆alkyl; each R⁵, R^5a, R^5b, R^5c, R^5d, R^5e, R^5f, R^5g and R^5h are independently selected from hydrogen and C1- C6alkyl; each R⁶ and R⁷ are independently selected from hydrogen and C₁-C₆alkyl; each R⁸ is independently selected from the group consisting of halo, -NH2, methyl and methoxy; R¹⁰ is selected from the group consisting of hydrogen, C₁-C₆alkyl, phenyl and benzyl; and R^10a is selected from the group consisting of hydrogen, C₁-C₆alkyl, phenyl and benzyl; said process comprising the steps: (a) Reacting a compound of formula (II)

wherein A is as defined above, with a metal amide base comprising a metal M¹ and a suitable additive, wherein M¹ is independently selected from the group consisting of Li, Na, K, Mg, Al, Zn, Cu and Mn; and (b) reacting the product of step (a) with a compound of formula (IV)

wherein R¹, R², Q and Z are as defined above; to give a compound of formula (V);

wherein A, Q, Z, R¹ and R² are as defined above; and (c) reacting the compound of formula (V) with an oxidizing reagent to give a compound of formula (I)

wherein A, R¹, R², Q and Z are as defined above. According to a second aspect of the invention, there is provided an intermediate compound of formula (V)

(V) wherein A, Q, Z, R¹ and R² are as defined herein. According to a third aspect of the invention, there is further provided an intermediate compound of formula (IV) or an agronomically acceptable salt or zwitterionic species thereof:

wherein Q, Z, R¹ and R² are as defined herein, with the proviso that Z is not selected from the group consisting of -CN, -C(O)OEt, -S(O)₂(OH) and -S(O)₂(OCH₂C(CH₃)₃). According to a fourth aspect of the invention, there is provided the use of a compound of formula (IV) or an agronomically acceptable salt or zwitterionic species thereof for preparing a compound of formula (I)

wherein Q, Z, R¹ and R² are as defined herein. As used herein, the term "C₁-C₆alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond. C₁-C₄alkyl and C₁- C₂alkyl are to be construed accordingly. Examples of C₁-C₆alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, and 1-dimethylethyl (t-butyl). The process of the present invention can be carried out in separate process steps, wherein the intermediate compounds can be isolated at each stage. Alternatively, the process can be carried out in a one-step procedure wherein the intermediate compounds produced are not isolated. Thus, it is possible for the process of the present invention to be conducted in a batch wise or continuous fashion. The compounds of formula (I) will typically be provided in the form of an agronomically acceptable salt, a zwitterion or an agronomically acceptable salt of a zwitterion. This invention covers processes to make all such agronomically acceptable salts, zwitterions and mixtures thereof in all proportions. For example a compound of formula (I) wherein Z comprises an acidic proton, may exist as a zwitterion, a compound of formula (I-I), or as an agronomically acceptable salt, a compound of formula (I-II) as shown below:

wherein, Y¹ represents an agronomically acceptable anion and j and k represent integers that may be selected from 1, 2 or 3, dependent upon the charge of the respective anion Y¹. A compound of formula (I) may also exist as an agronomically acceptable salt of a zwitterion, a compound of formula (I-III) as shown below:

wherein, Y¹ represents an agronomically acceptable anion, M represents an agronomically acceptable cation (in addition to the pyridazinium cation) and the integers j, k and s may be selected from 1, 2 or 3, dependent upon the charge of the respective anion Y¹ and respective cation M. Suitable agronomically acceptable salts of the present invention, represented by an anion Y¹, include but are not limited chloride, bromide, iodide, fluoride, 2-naphthalenesulfonate, acetate, adipate, methoxide, ethoxide, propoxide, butoxide, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, butylsulfate, butylsulfonate, butyrate, camphorate, camsylate, caprate, caproate, caprylate, carbonate, citrate, diphosphate, edetate, edisylate, enanthate, ethanedisulfonate, ethanesulfonate, ethylsulfate, formate, fumarate, gluceptate, gluconate, glucoronate, glutamate, glycerophosphate, heptadecanoate, hexadecanoate, hydrogen sulfate, hydroxide, hydroxynaphthoate, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methanedisulfonate, methylsulfate, mucate, myristate, napsylate, nitrate, nonadecanoate, octadecanoate, oxalate, pelargonate, pentadecanoate, pentafluoropropionate, perchlorate, phosphate, propionate, propylsulfate, propylsulfonate, succinate, sulfate, tartrate, tosylate, tridecylate, triflate, trifluoroacetate, undecylinate and valerate. Suitable cations represented by M include, but are not limited to, metals, conjugate acids of amines and organic cations. Examples of suitable metals include aluminium, calcium, cesium, copper, lithium, magnesium, manganese, potassium, sodium, iron and zinc. Examples of suitable amines include allylamine, ammonia, amylamine, arginine, benethamine, benzathine, butenyl-2-amine, butylamine, butylethanolamine, cyclohexylamine, decylamine, diamylamine, dibutylamine, diethanolamine, diethylamine, diethylenetriamine, diheptylamine, dihexylamine, diisoamylamine, diisopropylamine, dimethylamine, dioctylamine, dipropanolamine, dipropargylamine, dipropylamine, dodecylamine, ethanolamine, ethylamine, ethylbutylamine, ethylenediamine, ethylheptylamine, ethyloctylamine, ethylpropanolamine, heptadecylamine, heptylamine, hexadecylamine, hexenyl-2-amine, hexylamine, hexylheptylamine, hexyloctylamine, histidine, indoline, isoamylamine, isobutanolamine, isobutylamine, isopropanolamine, isopropylamine, lysine, meglumine, methoxyethylamine, methylamine, methylbutylamine, methylethylamine, methylhexylamine, methylisopropylamine, methylnonylamine, methyloctadecylamine, methylpentadecylamine, morpholine, N,N-diethylethanolamine, N- methylpiperazine, nonylamine, octadecylamine, octylamine, oleylamine, pentadecylamine, pentenyl-2- amine, phenoxyethylamine, picoline, piperazine, piperidine, propanolamine, propylamine, propylenediamine, pyridine, pyrrolidine, sec-butylamine, stearylamine, tallowamine, tetradecylamine, tributylamine, tridecylamine, trimethylamine, triheptylamine, trihexylamine, triisobutylamine, triisodecylamine, triisopropylamine, trimethylamine, tripentylamine, tripropylamine, tris(hydroxymethyl)aminomethane, and undecylamine. Examples of suitable organic cations include benzyltributylammonium, benzyltrimethylammonium, benzyltriphenylphosphonium, choline, tetrabutylammonium, tetrabutylphosphonium, tetraethylammonium, tetraethylphosphonium, tetramethylammonium, tetramethylphosphonium, tetrapropylammonium, tetrapropylphosphonium, tributylsulfonium, tributylsulfoxonium, triethylsulfonium, triethylsulfoxonium, trimethylsulfonium, trimethylsulfoxonium, tripropylsulfonium and tripropylsulfoxonium. Preferred compounds of formula (I), wherein Z comprises an acidic proton, can be represented as either (I-I) or (I-II). For compounds of formula (I-II) emphasis is given to salts when Y¹ is chloride, bromide, iodide, hydroxide, bicarbonate, acetate, pentafluoropropionate, triflate, trifluoroacetate, methylsulfate, tosylate, benzoate and nitrate, wherein j and k are 1. Preferably, Y¹ is chloride, bromide, iodide, hydroxide, bicarbonate, acetate, trifluoroacetate, methylsulfate, tosylate, benzoate and nitrate, wherein j and k are 1. Thus where a compound of formula (I) is drawn in protonated form herein, the skilled person would appreciate that it could equally be represented in unprotonated or salt form with one or more relevant counter ions. Compounds of formula (I) wherein m is 0 may be represented by a compound of formula (I-Ia) as shown below:

wherein R¹, R², A and Z are as defined for compounds of formula (I). Compounds of formula (I) wherein m is 1 may be represented by a compound of formula (I-Ib) as shown below:

wherein R¹, R², R^1a, R^2b, A and Z are as defined for compounds of formula (I). Compounds of formula (I) wherein m is 2 may be represented by a compound of formula (I-Ic) as shown below:

wherein R¹, R², R^1a, R^2b, A and Z are as defined for compounds of formula (I). The following list provides definitions, including preferred definitions, for substituents m, n, o, q, A, M¹, M², Q, X¹, X², Z, Z², R¹, R², R^1a, R^2b, R², R³, R⁴, R^4a, R^4b, R⁵, R^5a, R^5b, R^5c, R^5d, R^5e, R^5f, R^5g, R^5h, R⁶, R⁷, R⁸, R¹⁰, R^10a, R¹², R^a, R^b and R^c with reference to the process according to the invention. For any one of these substituents, any of the definitions given below may be combined with any definition of any other substituent given below or elsewhere in this document. A is a 6-membered heteroaryl selected from the group consisting of formula A-I to A-VII below

wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I), p is 0, 1 or 2 (preferably, p is 0 or 1, more preferably, p is 0). Preferably, A is a 6-membered heteroaryl selected from the group consisting of formula A-I, A-II, A-III, A-IV, A-V and A-VII below

wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I), p is 0, 1 or 2 (preferably, p is 0 or 1, more preferably, p is 0). More preferably, A is a 6-membered heteroaryl selected from the group consisting of formula A-Ia, A- IIa, A-IIIa, A-IVa, A-Va and A-VIIa below

a _. wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I). Even more preferably, A is a 6-membered heteroaryl selected from the group consisting of formula A- Ia, A-IIa, A-IIIa and A-VIIa below

wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I). Even more preferably still, A is a 6-membered heteroaryl selected from the group consisting of formula A-Ia, A-IIIa and A-VIIa below

_. wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I). Yet even more preferably still, A is the group A-Ia or A-IIIa. Most preferably, A is the group A-Ia. R¹ is hydrogen or methyl, preferably R¹ is hydrogen. R² is hydrogen or methyl, preferably R² is hydrogen. In a preferred embodiment R¹ and R² are hydrogen. Q is (CR^1aR^2b)m. m is 0, 1 or 2, preferably m is 1 or 2. Most preferably, m is 1. each R^1a and R^2b are independently selected from the group consisting of hydrogen, methyl, –OH and –NH2. More preferably, each R^1a and R^2b are independently selected from the group consisting of hydrogen and methyl. Most preferably R^1a and R^2b are hydrogen. Z is selected from the group consisting of –CN, -CH₂OR³, -CH(OR⁴)(OR^4a), -C(OR⁴)(OR^4a)(OR^4b), – C(O)OR¹⁰, -C(O)NR⁶R⁷ and -S(O)₂OR¹⁰. Preferably, Z is selected from the group consisting of –CN, - CH₂OR³, –C(O)OR¹⁰, -C(O)NR⁶R⁷ and -S(O)₂OR¹⁰. More preferably, Z is selected from the group consisting of –CN, -CH₂OH, –C(O)OR¹⁰, -C(O)NH₂ and -S(O)₂OR¹⁰. Even more preferably, Z is selected from the group consisting of –CN, -CH₂OH, –C(O)OR¹⁰ and -S(O)₂OR¹⁰. Yet even more preferably still, Z is selected from the group consisting of –CN, –C(O)OR¹⁰ and -S(O)₂OR¹⁰. Yet even more preferably still, Z is selected from the group consisting of –CN, -C(O)OCH₂CH₃, -C(O)OC(CH₃)₃, –C(O)OH and - S(O)₂OH. Yet further more preferably still, Z is selected from the group consisting of –CN, - C(O)OCH₂CH₃, -C(O)OC(CH₃)₃ and –C(O)OH. Even further more preferably still, Z is –CN or - C(O)OCH₂CH₃. In an alternative embodiment Z is selected from the group consisting of a group of formula Za, Zb, Zc, Zd, Ze and Zf below

wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I). Preferably, Z is selected from the group consisting of a group of formula Za, Zb, Zd, Ze and Zf. More preferably, Z is selected from the group consisting of a group of formula Za, Zd and Ze. In another embodiment of the invention Z is –C(O)OR¹⁰ and R¹⁰ is hydrogen or C₁-C₆alkyl. Preferably Z is -C(O)OCH₂CH₃. In another embodiment of the invention Z is selected from the group consisting of –CN, -CH₂OH, – C(O)OR¹⁰ and -S(O)₂OR¹⁰, or Z is selected from the group consisting of a group of formula Za, Zd and Ze. Preferably, Z is selected from the group consisting of –CN, -CH₂OH, –C(O)OR¹⁰, -S(O)₂OR¹⁰ and - CH=CH₂. Z² is -C(O)OH or -S(O)₂OH. Preferably, Z² is -C(O)OH. R³ is hydrogen or -C(O)OR^10a. Preferably, R³ is hydrogen. Each R⁴, R^4a and R^4b are independently selected from C₁-C₆alkyl. Preferably, each R⁴, R^4a and R^4b are methyl. Each R⁵, R^5a, R^5b, R^5c, R^5d, R^5e, R^5f, R^5g and R^5h are independently selected from hydrogen and C1- C6alkyl. More preferably, each R⁵, R^5a, R^5b, R^5c, R^5d, R^5e, R^5f, R^5g and R^5h are independently selected from hydrogen and methyl. Most preferably, each R⁵, R^5a, R^5b, R^5c, R^5d, R^5e, R^5f, R^5g and R^5h are hydrogen. Each R⁶ and R⁷ are independently selected from hydrogen and C₁-C₆alkyl. Preferably, each R⁶ and R⁷ are independently hydrogen or methyl. Most preferably, each R⁶ and R⁷ are hydrogen. Each R⁸ is independently selected from the group consisting of halo, -NH2, methyl and methoxy. Preferably, R⁸ is halo (preferably, chloro or bromo) or methyl. More preferably, R⁸ is chloro or bromo. R¹⁰ is selected from the group consisting of hydrogen, C₁-C₆alkyl, phenyl and benzyl. Preferably, R¹⁰ is hydrogen or C₁-C₆alkyl. More preferably, R¹⁰ is selected from the group consisting of hydrogen, methyl, ethyl, iso-propyl, 2,2-dimethylpropyl and tert-butyl. R^10a is selected from the group consisting of hydrogen, C₁-C₆alkyl, phenyl and benzyl. Preferably, R10a is selected from the group consisting of hydrogen, C₁-C₆alkyl and phenyl. More preferably, R^10a is hydrogen or C₁-C₆alkyl. In one embodiment of the invention, R¹⁰ is ethyl or tert-butyl. Preferably, R¹⁰ is ethyl. M¹ is independently selected from the group consisting of Li (Lithium), Na (Sodium), K (Potassium), Mg (Magnesium), Al (Aluminium), Zn (Zinc), Cu (Copper) and Mn (Manganese). Preferably, M¹ is independently selected from the group consisting of Li, Mg, Al, Zn and Cu. More preferably, M¹ is independently selected from the group consisting of Li, Mg and Zn. More preferably, M¹ is Zn or Mg. Most preferably, M¹ is Zn. Preferably, the compound of formula (I) is further subjected to a hydrolysis, oxidation and/or a salt exchange (i.e converted) to give an agronomically acceptable salt of formula (Ia) or a zwitterion of formula (Ib),

wherein Y¹ represents an agronomically acceptable anion and j and k represent integers that may be selected from 1, 2 or 3 (preferably, Y¹ is Cl- and j and k are 1), and A, R¹, R² and Q are as defined herein and Z² is -C(O)OH or -S(O)₂OH (the skilled person would appreciate that Z^2- represents -C(O)O- or - S(O)₂O-). More preferably, the the compound of formula (I) is further subjected to a hydrolysis, oxidation and/or a salt exchange (i.e converted) to give a compound of formula (Ia),

wherein Y¹ represents an agronomically acceptable anion and j and k represent integers that may be selected from 1, 2 or 3 (preferably, Y¹ is Cl- and j and k are 1), and A, R¹, R² and Q are as defined herein and Z² is -C(O)OH. Where a compound of formula (I) is drawn in protonated form herein (R¹⁰ is hydrogen), the skilled person would appreciate that it could equally be represented in unprotonated or salt form with one or more relevant counter ions. Preferably, in a compound of formula (Ia) Y¹ is chloride, bromide, iodide, hydroxide, bicarbonate, acetate, trifluoroacetate, methylsulfate, tosylate, benzoate and nitrate, wherein j and k are 1. More preferably, in a compound of formula (Ia) Y¹ is Cl- and j and k are 1. The present invention further provides an intermediate compound of formula (V):

wherein A, Q, Z, R¹ and R² are as defined herein. Preferably, in an intermediate compound of formula (V), A is a 6-membered heteroaryl selected from the group consisting of formula A-Ia, A-IIa, A-IIIa and A- VIIa below

wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (V) (preferably, A is the group A-Ia or A-IIIa); R¹ is hydrogen; R² is hydrogen; Q is (-CH₂-)m; m is 0 or 1; Z is selected from the group consisting of –CN, -CH₂OH, –C(O)OR¹⁰ or -S(O)₂OR¹⁰; and R¹⁰ is selected from the group consisting of hydrogen and C₁-C₆alkyl. More preferably, the intermediate compound of formula (V) is selected from the group consisting of a compound of formula (V-I), (V-II), (V-III), (V-IV), (V-V), (V-VI), (V-VII), (V-VIII), (V-IX) and (V-X) below,

wherein R¹⁰ is selected from the group consisting of hydrogen and C₁-C₆alkyl (preferably hydrogen, methyl, ethyl, iso-propyl, 2,2-dimethylpropyl and tert-butyl). In one embodiment of the invention the compound of formula (V) is selected from the group consisting of a compound of formula (V-Va), (V-Vb), (V-Vc), (V-VIa), (V-VIb) and (V-VIc) below (preferably, V-Va or V-VIa)

In one embodiment of the invention there is provided the use of a compound of formula (IV) or an agronomically acceptable salt or zwitterionic species thereof for preparing a compound of formula (I)

wherein Q, Z, R¹ and R² are as defined herein. Preferably, there is provided the use of a compound of formula (IV) or an agronomically acceptable salt or zwitterionic species thereof for preparing a compound of formula (I), wherein R¹ is hydrogen; R² is hydrogen; Q is (-CH₂-)m; m is 0 or 1; Z is selected from the group consisting of –CN, -CH₂OH, –C(O)OR¹⁰ or -S(O)₂OR¹⁰; and R¹⁰ is selected from the group consisting of hydrogen and C₁-C₆alkyl. More preferably, there is provided the use of a compound of formula (IV) or an agronomically acceptable salt or zwitterionic species thereof for preparing a compound of formula (I), wherein the compound of formula (IV) is selected from the group consisting of a compound of formula (IV-I), (IV-II), (IV-III), (IV-IV) and (IV-V) below,

wherein R¹⁰ is selected from the group consisting of hydrogen and C₁-C₆alkyl (preferably hydrogen, methyl, ethyl, iso-propyl, 2,2-dimethylpropyl and tert-butyl). Even more preferably, there is provided the use of a compound of formula (IV) or an agronomically acceptable salt or zwitterionic species thereof for preparing a compound of formula (I), wherein the compound of formula (IV) is selected from the group consisting of a compound of formula (IV-IIIa) or (IV-IIIb) below

The present invention further provides an intermediate compound of formula (IV) or an agronomically acceptable salt or zwitterionic species thereof:

wherein Q, Z, R¹ and R² are as defined herein, with the proviso that Z is not selected from the group consisting of -CN, -C(O)OEt, -S(O)₂(OH) and -S(O)₂(OCH₂C(CH₃)₃). The skilled person would appreciate that the compounds of formula (IV) will typically be provided in the form of an agronomically acceptable salt, a zwitterion or an agronomically acceptable salt of a zwitterion. This invention covers processes using all such agronomically acceptable salts, zwitterions and mixtures thereof in all proportions. For example a compound of formula (IV) wherein Z comprises an acidic proton, may exist as a zwitterion, a compound of formula (IV-a), or as an agronomically acceptable salt, a compound of formula (IV-b) as shown below: Y1 k

wherein, Y¹ represents an agronomically acceptable anion and j and k represent integers that may be selected from 1, 2 or 3, dependent upon the charge of the respective anion Y¹. Suitable agronomically acceptable salts for a compound of formula (IV), represented by an anion Y¹, are as described above. Suitable cations for a compound of formula (IV) represented by M are as described above. Preferred compounds of formula (IV), wherein Z comprises an acidic proton, can be represented as either (IV-a) or (IV-b). For compounds of formula (IV-b) emphasis is given to salts when Y¹ is chloride, bromide, iodide, hydroxide, bicarbonate, acetate, pentafluoropropionate, tetrafluoroborate, triflate, trifluoroacetate, methylsulfate, mesylate, tosylate, benzoate and nitrate, wherein j and k are 1. Preferably, Y¹ is selected from the group consisting of chloride, bromide, iodide, hydroxide, bicarbonate, acetate, tetrafluoroborate, trifluoroacetate, methylsulfate, mesylate, tosylate, benzoate and nitrate, wherein j and k are 1. More preferably, Y¹ is selected from the group consisting of chloride, bromide, tetrafluoroborate and mesylate. Thus where a compound of formula (IV) is drawn in protonated form herein, the skilled person would appreciate that it could equally be represented in unprotonated or salt form with one or more relevant counter ions. In one embodiment of the invention, the compound of formula (IV) is selected from the group consisting of a compound of formula (IV-aa), (IV-bb), (IV-cc), (IV-dd), (IV-ee), (IV-ff), (IV-gg), (IV-hh), (IV-jj), (IV-kk) and (IV-mm) below

Wherein, Y¹ is selected from the group consisting of chloride, bromide, iodide, hydroxide, bicarbonate, acetate, trifluoroacetate, tetrafluoroborate, methylsulfate, hydrogensulfate, mesylate, tosylate, benzoate and nitrate, and j and k are 1. Preferably, Y¹ is selected from the group consisting of chloride, bromide, trifluoroacetate, tetrafluoroborate and mesylate and j and k are 1. Compounds of formula (IV) and compounds of formula (II) are are either known in the literature or may be prepared by known literature methods. Compounds of formula (IV) and compounds of formula (II) are are either known in the literature or may be prepared by known literature methods. The skilled person would envisage that structures such as a compound of formula (III) could be formed from the reaction conditions described in process step (a) but that the exact structures formed are not always known and depend upon the conditions used. Typically a compound of formula (III) may be described as

wherein A is as defined above and M¹, M², X¹, X², n, o and q are as defined below. M¹ is independently selected from the group consisting of Li, Na, K, Mg, Al, Zn, Cu and Mn. X¹ is independently selected from the group consisting of F, Cl, Br, I, CN, SCN, NCO, ClO₃, ClO₄, BrO₃, BrO₄, NO₃, BF₄, PF₆, R^aCO₂, OR^b, R^cSO₃ and C₁-C₆alkyl. Preferably, X¹ is independently selected from the group consisting of F, Cl, Br, I, CN, ClO3, ClO4, BrO₃, BrO₄, R^aCO₂, OR^b, R^cSO₃ and C₁-C₆alkyl. More preferably, X¹ is independently selected from the group consisting of F, Cl, Br, I, R^aCO2, OR^b and R^cSO3. Even more preferably, X¹ is independently selected from the group consisting of Cl, Br, I and R^aCO2. Yet even more preferably, X¹ is independently selected from the group consisting of Cl, Br and R^aCO2. Yet even more preferably still X¹ is independently selected from the group consisting of Cl, Br and ((CH₃)₃C)CO₂. M² is independently selected from the group consisting of Li, Na, K, Mg, Ca, Mn and Zn. Preferably, M² is independently selected from the group consisting of Li, Na, K, Mg, Mn and Zn. More preferably, M² is independently selected from the group consisting of Li, Na, K, Mg, and Zn. Even more preferably, M² is independently selected from the group consisting of Li, Mg, and Zn. Most preferably, M² is Li. X² is independently selected from the group consisting of F, Cl, Br, I, CN, SCN, NCO, ClO₃, ClO₄, BrO₃, BrO₄, IO₃, IO₄, NO₃, BF₄, PF₆, R^aCO₂, OR^b, R^cS(O)₂O. Preferably, X² is independently selected from the group consisting of F, Cl, Br, I, CN, ClO₃, ClO₄, BrO₃, BrO₄, R^aCO₂, OR^b and R^cSO₃. More preferably, X² is independently selected from the group consisting of F, Cl, Br, I, R^aCO₂, OR^b and R^cSO₃. Even more preferably, X² is independently selected from the group consisting of Cl, Br, I and R^aCO₂. Yet even more preferably, X² is independently selected from the group consisting of Cl, Br and R^aCO₂. Yet even more preferably still X² is independently selected from the group consisting of Cl, Br and ((CH₃)₃C)CO₂. Further more preferably still, X² is Cl or Br. Most preferably X² is Cl. n is 1, 2 or 3. Preferably, n is 1 or 2. Most preferably, n is 1. o is 0, 1 or 2. Preferably o is 0 or 1. q is 0 or 1. R^a is C₁-C₆alkyl or phenyl. Preferably R^a is C₁-C₆alkyl. More preferably R^a is tert-butyl. R^b is C₁-C₆alkyl or phenyl. Preferably, R^b is C₁-C₆alkyl. R^c is selected from the group consisting of C₁-C₆alkyl, trifluoromethyl and p-toluene. Preferably, R^c is selected from the group consisting of methyl, trifluoromethyl and p-toluene. More preferably, R^c is methyl or trifluoromethyl. Preferably, the compound of formula (III) may be described as wherein,

A is a 6-membered heteroaryl selected from the group consisting of formula A-Ia, A-IIIa and A-VIIa below

wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (III); M¹ is independently selected from the group consisting of Li, Mg and Zn (preferably, Zn); X¹ is independently selected from the group consisting of F, Cl, Br, I, CN, SCN, NCO, ClO3, ClO4, BrO3, BrO₄, NO₃, BF₄, PF₆, R^aCO₂, OR^b, R^cSO₃ and C₁-C₆alkyl (preferably, X¹ is independently selected from the group consisting of Cl, Br, I and R^aCO₂, more preferably, X¹ is independently selected from the group consisting of Cl, Br and R^aCO₂); M² is independently selected from the group consisting of Li, Mg, and Zn; X² is independently selected from the group consisting of F, Cl, Br, I, CN, ClO₃, ClO₄, BrO₃, BrO₄, R^aCO₂, OR^b and R^cSO₃ (preferably, X² is independently selected from the group consisting of Cl, Br, I, R^aCO₂, OR^b and R^cSO₃, more preferably, X² is independently selected from the group consisting of F, Cl, Br, I and R^aCO2, even more preferably, X² is independently selected from the group consisting of Cl, Br and R^aCO2); n is 1 or 2; o is 0 or 1; q is 0 or 1; R^a is C₁-C₆alkyl; R^b is C₁-C₆alkyl; R^c is selected from the group consisting of methyl, trifluoromethyl and p-toluene. More preferably, the compound of formula (III) is selected from the group consisting of a compound of formula (III-i), (III-ii), (III-iii), (III-iv), (III-v) and (III-vi) below,

Wherein X¹ is independently selected from the group consisting of F, Cl, Br, I, CN, SCN, NCO, ClO₃, ClO₄, BrO₃, BrO₄, NO₃, BF₄, PF₆, R^aCO₂, OR^b, R^cSO₃ and C₁-C₆alkyl (preferably, X¹ is independently selected from the group consisting of Cl, Br, I and R^aCO2, more preferably, X¹ is independently selected from the group consisting of Cl, Br and R^aCO2). Even more preferably, the compound of formula (III) is selected from the group consisting of a compound of formula (III-b), (III-c), (III-d) and (III-e) below

Even more preferably still, the compound of formula (III) is a compound of formula (III-b) or (III-c) below

Scheme 1 below describes the reactions of the invention in more detail. The substituent definitions are as defined herein. Scheme 1:

Step (a): The product of step (a) can be prepared by reacting a compound of formula (II)

wherein A is as defined herein, with a metal amide base comprising a metal M¹ and a suitable additive, wherein M¹ is as defined herein. Typically in this process of the invention such metal amide bases contain a metal for example in a covalent bond with a substituted nitrogen atom optionally complexed with one or more metal salts (for example but not limited to lithium chloride, lithium bromide, magnesium chloride and magnesium bromide). More preferably, in the process of the invention the metal amide base is a base of formula (VI) or (VIa)

wherein in a compound of formula (VI) or (VIa), each R¹¹ and R¹² are independently selected from the group consisting of C₁-C₆alkyl (preferably isopropyl), C4-C7cycloalkyl (preferably cyclohexyl) and C₁-C₆alkoxyalkyl, or R¹¹ and R¹² together with the nitrogen atom to which they are attached for a 5- to 6-membered heterocyclyl optionally substituted by one or more methyl groups (preferably, R¹¹ and R¹² form a 2,2,6,6- tetramethylpiperidinyl group); and wherein A, M¹, X¹, M², X², n, o and q are as defined herein. More preferably in the process of the invention the metal amide base is a metal tetramethylpiperidine (TMP) base. Even more preferably, the metal amide base is a TMPZinc or a TMPMagnesium reagent. Yet even more preferably, the metal amide base is selected from the group consisting of TMPMgCl.LiCl (2,2,6,6-Tetramethylpiperidinylmagnesium chloride lithium chloride complex), (TMP)₂Zn (bis(2,2,6,6- tetramethylpiperidinyl)zinc), (TMP)₂Zn.MgCl₂.LiCl (bis(2,2,6,6-tetramethylpiperidinyl)zinc and lithium chloride and magnesium chloride complex), TMPZnCl.LiCl (2,2,6,6-Tetramethylpiperidinylzinc chloride lithium chloride complex) and TMPZnBr.LiBr (2,2,6,6-Tetramethylpiperidinylzinc bromide lithium bromide complex). Yet even more preferably still, the metal amide base is selected from the group consisting of (TMP)₂Zn.MgCl₂.LiCl, TMPZnCl.LiCl and TMPZnBr.LiBr. Yet even further more preferably still, the metal amide base is TMPZnCl.LiCl or TMPZnBr.LiBr. Most preferably, the metal amide base is TMPZnBr.LiBr. Preferably, the metal amide base is used in an amount of from 1 to 5 equivalents, relative to the number of moles of the compound of formula (II). More preferably, from 1 to 3 equivalents, even more preferably from 1 to 2 equivalents. In the process of the invention this step is carried out in the presence of a sutiable additive (preferably a lewis acid), such as, but not limited to, BF3.OEt, MgBr₂, ZnBr₂, ZnCl₂, MgCl₂, Mg(OTf)₂, Zn(OTf)₂, Sc(OTf)₃, AlCl₃, AlBr₃ and FeCl₃. More preferably, the suitable additive is selected from the group consisting of BF₃.OEt, MgBr₂, ZnBr₂, ZnCl₂, Zn(OTf)₂ and AlCl₃. Even more preferably, the suitable additive is selected from the group consisting of BF₃.OEt, MgBr₂, ZnBr₂ and Zn(OTf)₂. Even more preferably still, the suitable additive is selected from the group consisting of BF₃.OEt, MgBr₂ and ZnBr₂. Most preferably, the suitable additive is MgBr₂. Preferably, the suitable additive is used in an amount of from 0.1 to 5 equivalents, relative to the number of moles of the compound of formula (II). More preferably, from 0.3 to 3 equivalents, even more preferably from 0.5 to 2 equivalents. Typically the process described in step (a) is carried out in a solvent, or mixture of solvents, such as but not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, diethylether, tert-butylmethylether, tert-amyl methyl ether, cyclopentyl methyl ether, dimethoxymethane, diethoxymethane, dipropoxy methane, 1,3- dioxolane, ethyl acetate, dimethyl carbonate, dichloromethane, dichloroethane, N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl pyrrolidone (NMP), acetonitrile, propionitrile, butyronitrile, benzonitrile (or derivative thereof e.g 1,4-dicyanobenzene), 1,4-dioxane or sulfolane. Preferably, step (a) is carried out in a solvent, or mixture of solvents, selected from tetrahydrofuran and 2-methyltetrahydrofuran (preferably, tetrahydrofuran). This step can be carried out at a temperature of from -78 ºC to 120 ºC, preferably, from -20 °C to 60 °C. More preferably, from -20 °C to 40 °C. Even more preferably, from 0 °C to 40 °C. This step may also me carried out under microwave irradiation. Preferably process step (a) of the present invention is carried out under an inert atmosphere, such as nitrogen or argon. The skilled person would appreciate that the suitable additive used in the process can facilitate the conversion of a compound of formula (II). The suitable additive may be used in stoichiometric or sub- stoichiometric or catalytic amounts. Step (b) Nucleophilic Addition: Compounds of formula (V) can be produced by reacting the product of step (a) with a compound of formula (IV) or an agronomically acceptable salt or zwitterionic species thereof

wherein R¹, R², Q and Z are as defined herein, to give a compound of formula (V)

wherein A, Q, Z, R¹ and R² are as defined herein. Typically the product of step (a) used in the process step (b) is produced in situ before carrying out the process described above. However, the skilled person would also appreciate that it may be possible to isolate the compound of the product of step (a) (for example a compound of formula (III)) before it is used in process step (b). Preferably process step (b) is carried out in the presence of a transition metal catalyst. Preferably the transition metal catalyst is a copper catalyst (for example a Cu (I) salt or a Cu (II) salt). More preferably, the copper catalyst is selected from the group consisting of copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) acetate, copper (II) acetate, copper (I) cyanide, copper (I) trifluoromethanesulfonate, copper (II) trifluoromethanesulfonate, copper (I) thiophenolate, copper (I) thiophene-2-carboxylate, copper (II) trifluoroacetate, copper (II) acetylacetonate, copper (II) naphthenate, copper (II) perchlorate, copper (II) tetrafluoroborate and copper (II) sulfate. Even more preferably, the copper catalyst is copper (I) iodide or copper (I) cyanide. Typically the process described in step (b) is carried out in a solvent, or mixture of solvents, such as but not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, diethylether, tert-butylmethylether, tert- amyl methyl ether, cyclopentyl methyl ether, dimethoxymethane, diethoxymethane, dipropoxy methane, 1,3-dioxolane, ethyl acetate, dimethyl carbonate, dichloromethane, dichloroethane, N,N- dimethylformamide, N,N-dimethylacetamide, N-methyl pyrrolidone (NMP), acetonitrile, propionitrile, butyronitrile, benzonitrile (or derivative thereof e.g 1,4-dicyanobenzene), 1,4-dioxane or sulfolane. This step reaction can be carried out at a temperature of from -78 ºC to 120 ºC, preferably, from -20 °C to 60 °C. More preferably, from -20 °C to 30 °C. Preferably process step (b) of the present invention is carried out under an inert atmosphere, such as nitrogen or argon. Step (c) Oxidation: The compound of formula (I) can be prepared by reacting a compound of formula (V):

wherein A, Q, Z, R¹ and R² are as defined herein, with an oxidizing reagent to give a compound of formula (I)

wherein A, R¹, R², Q and Z are as defined herein. Typically in this process step (c) examples of such oxidizing agents include but are not limited to, hydrogen peroxide, hydrogen peroxide and a suitable catalyst (for example, but are not limited to: TiCl3, Mn(OAc)3.2H2O and a bipyridine ligand, VO(acac)₂ and a bidentate ligand, Ti(OiPr4) and a bidentate ligand, Polyoxymetalates, Na2WO4 together with additives such as PhPO3H2 and CH₃(n-C8H17)3NHSO4, lanthanide catalysts such as Sc(OTf)3, organic molecules can also act as catalysts, for example flavins), chlorine, with or without a suitable catalyst (as listed above) , bromine with or without a suitable catalyst (as listed above), organic hydroperoxides (for example peracetic acid, performic acid, t- Butylhydroperoxide, cumylhydroperoxide, MCPBA), an organic hydroperoxide prepared in situ (for example from the reaction of H2O2 and a carboxylic acid + a suitable catalyst), organic peroxides (for example benzoyl peroxide, or di-terbutylperoxide), amine N-oxides (for example N-Methylmorpholine Oxide, pyridine N-oxide or triethylamine N-oxide peroxide derivative), inorganic oxidants (NaIO4, KMnO4, MnO2, CrO3), inorganic oxidants prepared in situ (for example, a Ru catalyst + an oxidant forms in situ RuO4 which maybe a capable oxidant), inorganic hydroperoxides, inorganic peroxides, dioxiranes (for example DMDO), oxone, oxygen (oxygen + a suitable catalyst such as NO2, or Cerric ammonium nitrate), air + a suitable catalyst (such systems can lead to the in-situ formation of peroxides and suitable catalysts can be for example, but not limited to, Fe(NO3)3-FeBr3), NaOCl (which may be used in conjunction with catalytic amounts of a stable radical such as (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), 4-hydroxy-TEMPO or 4-acetylamino-TEMPO, optionally catalytic amounts of sodium bromide may also be added ), NaOBr, HNO3, biocatalysts such as peroxidases and monooxygenases, nitrosyl chloride (prepared in situ), N-chlorophthalimide, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetrachloro-1,4-benzoquinone (chloranil), potassium permanganate, manganese dioxide and iodine. Preferably, the oxidizing agent in step (c) is selected from the group consisting of N-chlorophthalimide, tetrachloro-1,4-benzoquinone (chloranil) and iodine. Typically the process described in step (c) is carried out in a solvent, or mixture of solvents, such as but not limited to, H2O, alchohols (such as MeOH, iPrOH, EtOH, BuOH, tBuOH, tert amyl alcohol), tetrahydrofuran, 2-methyltetrahydrofuran, diethylether, tert-butylmethylether, tert-amyl methyl ether, cyclopentyl methyl ether, dimethoxymethane, diethoxymethane, dipropoxy methane, 1,3-dioxolane, ethyl acetate, dimethyl carbonate, dichloromethane, dichloroethane, N,N-dimethylformamide, N,N- dimethylacetamide, N-methyl pyrrolidone (NMP), acetonitrile, propionitrile, butyronitrile, benzonitrile (or derivative thereof e.g 1,4-dicyanobenzene), 1,4-dioxane or sulfolane. Preferably process step (c) of the present invention is carried out under an inert atmosphere, such as nitrogen or argon. The skilled person would appreciate that the temperature of the process according to the invention can vary in each of steps (a), (b) and (c). Furthermore, this variability in temperature may also reflect the choice of solvent used. Preferably, the process of the present invention is carried out under an inert atmosphere, such as nitrogen or argon. In a preferred embodiment of the invention the compound of formula (I) is further converted (for example via a hydrolysis, oxidation and/or a salt exchange as shown in scheme 2 below) to give an agronomically acceptable salt of formula (Ia) or a zwitterion of formula (Ib),

wherein Y¹ represents an agronomically acceptable anion and j and k represent integers that may be selected from 1, 2 or 3 (preferably, Y¹ is Cl- and j and k are 1), and A, R¹, R² and Q are as defined herein and Z² is -C(O)OH or -S(O)₂OH (the skilled person would appreciate that Z^2- represents -C(O)O- or - S(O)₂O-). Preferably in a compound of formula (Ia) Y¹ is Cl- and j and k are 1.

Step (f) Hydrolysis: The hydrolysis can be performed using methods known to a person skilled in the art. The hydrolysis is typically performed using a suitable reagent, including, but not limited to aqueous sulfuric acid, concentrated hydrochloric acid or an acidic ion exchange resin. Typically, the hydrolysis is carried out using aqueous hydrochroric acid, optionally in the presence of an additional suitable solvent, at a suitable temperature from 0 ºC to 120 ºC (preferably, from 20 °C to 100 °C). Step (g) Salt Exchange: The salt exchange of a compound of formula (I) to a compound of formula (Ia) can be performed using methods known to a person skilled in the art and refers to the process of converting one salt form of a compound into another (anion exchange), for example coverting a trifluoroacetate (CF3CO2-) salt to a chloride (Cl-) salt. The salt exchange is typically performed using an ion exchange resin or by salt metathesis. Salt metathesis reactions are dependent on the ions involved, for example a compound of formula (I) wherein the agronomically acceptable salt is a hydrogen sulfate anion (HSO4-) may be switched to a compound of formula (Ia) wherein Y¹ is a chloride anion (Cl-) by treatment with an aqueous solution of barium chloride (BaCl2) or calcium chloride (CaCl2). Preferably, the salt exchange of a compound of formula (I) to a compound of formula (Ia) is performed with barium chloride. In a preferred embodiment of the invention there is provided a process for the preparation of a compound of formula (I) or an agronomically acceptable salt or zwitterionic species thereof:

wherein A is a 6-membered heteroaryl of formula A-Ia or A-IIIa (preferably A-Ia) below

wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I); and R¹ is hydrogen; R² is hydrogen; Q is (CR^1aR^2b)m; m is 1; each R^1a and R^2b are hydrogen; Z is selected from the group consisting of –CN, -CH₂OH, –C(O)OR¹⁰, and -S(O)₂OR¹⁰ (preferably –CN, –C(O)OR¹⁰, and -S(O)₂OR¹⁰); and R¹⁰ is selected from the group consisting of hydrogen and C₁-C₆alkyl (preferably, methyl, ethyl or tert- butyl); said process comprising the steps: (a) reacting a compound of formula (II-i) or (II-ii) (preferably, II-i)

with a zinc tetramethylpiperidine (TMP) base, (preferably, TMPZnCl.LiCl or TMPZnBr.LiBr, more preferably TMPZnBr.LiBr) and a lewis acid (preferably selected from the group consisting of BF3.OEt, MgBr2, ZnBr2, ZnCl2, Zn(OTf)₂ and AlCl3, more preferably selected from the group consisting of BF3.OEt, MgBr2, ZnBr2 and Zn(OTf)₂, even more preferably MgBr2) and (b) reacting the product of step (a) with a compound of formula (IV) or an agronomically acceptable salt or zwitterionic species thereof (preferably in the presence of a a copper catalyst (for example a Cu (I) salt or a Cu (II) salt), more preferably, the copper catalyst is copper (I) iodide or copper (I) cyanide),

wherein A, Q, Z, R¹ and R² are as defined above; and (c) reacting the compound of formula (V) with an oxidizing reagent (preferably, the oxidizing agent is selected from the group consisting of N-chlorophthalimide, tetrachloro-1,4- benzoquinone (chloranil) and iodine) to give a compound of formula (I) or an agronomically acceptable salt or zwitterionic species thereof, wherein

A, R¹, R², Q and Z are as defined above. Surprisingly it has been found that the use of a zinc tetramethylpiperidine (TMP) base may provide a more stable organometallic reagent and achieve higher regioselectivity at the desired position of the 6- membered heteroaryl (A). Examples: The following examples further illustrate, but do not limit, the invention. Those skilled in the art will promptly recognise appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques. The following abbreviations are used: s = singlet; br s = broad singlet; d = doublet; dd = double doublet; dt = double triplet; t = triplet, tt = triple triplet, q = quartet, quin = quintuplet, sept = septet; m = multiplet; GC = gas chromatography, RT = retention time, Ti = internal temperature, MH⁺ = molecular mass of the molecular cation, M = molar, Q¹HNMR = quantitative ¹HNMR, RT = room temperature, UFLC = Ultra- fast liquid chromatography. ¹H NMR spectra are recorded at 400 MHz unless indicated otherwise and chemical shifts are recorded in ppm. LCMS Methods: Standard: Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions, Capillary: 3.00 kV, Cone range: 30 V, Extractor: 2.00 V, Source Temperature: 150°C, Desolvation Temperature: 350°C, Cone Gas Flow: 50 l/h, Desolvation Gas Flow: 650 l/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment , diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 µm, 30 x 2.1 mm, Temp: 60 °C, DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A = water + 5% MeOH + 0.05 % HCOOH, B= Acetonitrile + 0.05 % HCOOH, gradient: 10-100% B in 1.2 min; Flow (ml/min) 0.85 Standard long: Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions), Capillary: 3.00 kV, Cone range: 30V, Extractor: 2.00 V, Source Temperature: 150°C, Desolvation Temperature: 350°C, Cone Gas Flow: 50 l/h, Desolvation Gas Flow: 650 l/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment , diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 µm, 30 x 2.1 mm, Temp: 60 °C, DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A = water + 5% MeOH + 0.05 % HCOOH, B= Acetonitrile + 0.05 % HCOOH, gradient: 10-100% B in 2.7 min; Flow (ml/min) 0.85 GENERAL 2-5 min: Instrumentation: Mass Spectrometer: 6410 Triple Quadruple Mass Spectrometer from Agilent Technologies HPLC: Agilent 1200 Series HPLC Optimized Mass Parameter: Ionisation method: Electrospray (ESI) Polarity: Positive and Negative Polarity Switch Scan Type: MS2 Scan Capillary (kV): 4.00 Fragmentor (V): 100.00 Gas Temperature (°C) 350 Gas Flow (L/min): 11 Nebulizer Gas (psi): 45 Mass range: 110 to 1000 Da DAD Wavelength range: 210 to 400 nm Optimized Chromatographic Parameter: Gradient conditions: Solvent A: Water with 0.1% formic acid : Acetonitrile : 95 : 5 v/v Solvent B: Acetonitrile with 0.1% formic acid Time (minutes) A (%) B (%) Flow rate (ml/min) 0 90 10 1.8 0.9 0 100 1.8 1.8 0 100 1.8 2.2 90 10 1.8 2.5 90 10 1.8 Column: KINETEX EVO C18 Column length: 50 mm Internal diameter of column: 4.6 mm Particle Size: 2.6 µ Column oven temperature: 40°C HSS T3 GENERAL 1-6 min: Instrumentation: Mass Spectrometer : Acquity SDS Mass Spectrometer from Waters HPLC: UPLC 'H' class Optimized Mass Parameter: Ionisation method: Electrospray (ESI) Polarity: Positive and Negative Polarity Switch Scan Type: Full Scan Capillary (kV): 3.00 Cone Voltage (V): 41.00 Source Temperature (°C): 150 Desolvation Gas Flow (L/Hr): 1000 Desolvation Temperature (°C): 500 Gas Flow @ Cone (L/Hr): 50 Mass range : 110 to 800 Da PDA Wavelength range: 210 to 400 nm Optimized Chromatographic parameter: Gradient conditions: Solvent A: Water with 0.1% formic acid : Acetonitrile : : 95 : 5 v/v Solvent B: Acetonitrile with 0.05% formic acid Time (minutes) A (%) B (%) Flow rate (ml/min) 0 90 10 0.8 0.2 50 50 0.8 0.7 0 100 0.8 1.3 0 100 0.8 1.4 90 10 0.8 1.6 90 10 0.8 Column: Acquity UPLC HSS T3 C18 Column length: 30 mm Internal diameter of column: 2.1 mm Particle Size: 1.8 µ Column oven temperature: 40°C GC Method: Method Set temperature: 70 °C 1. Hold 70 °C for 30 sec 2. Heat from 70 °C to 250 °C (ramp of 50 °C/min) 3. Hold 250 °C for 5 min Inlet N2 carrier gas (in general, not only for inlet) Inlet temperature: 250 °C Pressure: 21.7 psi Flow: 94.2 mL/min Split ratio: 20.1 Split Flow: 87.6 mL/min Column Name: OPTIMA 5 – 0.25 μm Length: 15 m; 0.25 mm ID Reference: 726056.15 Pressure: 21.7 psi Flow: 4.4 mL/min (constant) Average velocity: 93 cm/sec Example 1: General procedure for preparation of 2-iodopyrimidine

Step 1: General procedure from preparation of MgBr2 solution in THF In a dry and argon flushed Schenk-flask, equipped with a magnetic stirring bar, were placed magnesium turnings (2.0 equiv) and dry THF (1 mL per mmol substrate). Then, 1,2- dibromoethane (1.0 equiv) was added as a solution in THF (1 M) and the resulting reaction mixture gently heated, till the evolution of a gas was observed. The temperature was maintained at 25–30 °C until no more gas evolved. The formed precipitate was solubilized by adding more THF (and gentle heating) and the magnesium turnings filtered off (under argon). The concentration of the resulting solution was determined by evaporating the solvent of 1 mL of the prepared solution and taking the weight. Step 2: General procedure for metalation of pyrimidine In a dry and argon flushed Schenk-flask, equipped with a magnetic stirring bar, was placed pyrimidine (37 μL, 0.5 mmol, 1.0 equiv). A solution of MgBr2 in THF (0.25–0.35 M, 1.0 equiv) was added at r.t. (25° C) and the resulting mixture stirred for 5 min (right after the addition a white precipitate formed). Next, TMPZnBr·LiBr (0.5 M, 1.75 mL, 0.875 mmol, 1.75 equiv) was added and the resulting reaction mixture stirred for 12 h (over night). Quenching of the formed organozinc reagent with iodine provided the 2- substituted pyrimidine in 97% isolated yield. Using the above procedure but with TMPZnCl.LiCl the 2-substituted pyrimidine was obtained in 88% isolated yield ¹H NMR (CDCl3, 400MHz): δ = 8.47 (d, J = 4.8 Hz, 1H), 7.32 (t, J = 4.8 Hz, 1H). ¹³C NMR (CDCl3, 400MHz): δ = 158.7, 129.7, 120.7 Using the above general procedure (where applicable) the following results were obtained in tables 1 and 2 below. Table 1. Screening of different TMP-bases and BF3·OEt2 as additive

Table 2. Screening of various additives

Example 2: Preparation of ethyl 3-pyridazin-1-ium-1-ylpropanoate bromide

To a solution of pyridazine (1 g) in acetonitrile (40 mL) was added ethyl 3-bromopropanoate (1.76 mL) and the reaction was stirred at 80°C for 25 hours. The mixture was concentrated and partitioned between dichloromethane and water. The aqueous layer was freeze dried to afford ethyl 3-pyridazin-1- ium-1-ylpropanoate bromide as a beige solid. 1H NMR (400MHz, D₂O) 9.68-9.92 (m, 1H), 9.43-9.56 (m, 1H), 8.43-8.69 (m, 2H), 5.15 (t, 2H), 4.11 (q, 2H), 3.27 (t, 2H), 1.16 (t, 3H) Example 3: Preparation of ethyl 3-pyridazin-1-ium-1-ylpropanoate 2,2,2-trifluoroacetate

To a solution of ethyl 3-pyridazin-1-ium-1-ylpropanoate bromide (0.88 g) in dry acetonitrile (6.7 mL), under nitrogen atmosphere, was added silver 2,2,2-trifluoroacetate (0.782 g). After 10 minutes the mixture was filtered through celite to remove the precipitate and washed through with dry tetrahydrofuran (6 mL). The filtrate was concentrated and the resulting residue was azeotroped with dry tetrahydrofuran (2x6 mL) to give ethyl 3-pyridazin-1-ium-1-ylpropanoate 2,2,2-trifluoroacetate as a black gum. ¹H NMR (400MHz, D2O) 9.99 (d, 1H), 9.60-9.66 (m, 1H), 8.58-8.78 (m, 2H), 5.07 (t, 2H), 4.07 (q, 2H), 3.19 (t, 2H), 1.16 (t, 3H) The trifluoroacetate ratio was confirmed in the NMR using 2,2,2-trifluoroethanol as standard. Example 4: Preparation of ethyl 3-pyridazin-1-ium-1-ylpropanoate chloride

Pyridazine (1.00g, 11.8 mmol, 94.6%) was dissolved in CH₃CN (10 mL/g, 191.0 mmol) at 24°C. Potassium Iodide (0.05 equiv., 0.5906 mmol, 99.9%) was added at 24°C. Ethyl 3-chloropropanoate (1.5 equiv., 17.7 mmol, 94.8%) was added at 24°C. The reaction mixture was heated at 82°C for 7h. Work up: Reaction mixture was cooled at RT and concentrated under reduced pressure. It was triturated with MTBE (10 mL/g). The mixture was decanted off and again triturated with MTBE (10 mL/g). The resulting solid was collected by filtration (1.77g, 83.4% purity, 57.6% yield). Crude weight: 1.77g, quant NMR purity- 83%. Chem. Yield 57% (contain 37% of SM) NMR data: 1H NMR (400 MHz, methanol-d4) δ ppm 1.25 (m, 2 H) 3.30 (m, 2 H) 4.13 (q, J=7.03 Hz, 2 H) 5.17 (br t, J=5.39 Hz, 2 H) 8.61 (br s, 1 H) 8.69 (br s, 1 H) 9.59 (br s, 1 H) 9.98 (br d, J=4.28 Hz, 1 H) Example 5: Preparation of ethyl 3-pyridazin-1-ium-1-ylpropanoate bromide

Equipment: 100mL 3 neck RBF along with Reflux condenser, Nitrogen inlet, thermometer. Procedure: 3 neck RBF was charged with pyridazine (10 g, 125 mmol, 95 mass%) then 1,4-dioxane (0.25mL/mmol). Ethyl 3-bromopropionate (23.7 g, 1.05 equiv., 131 mmol, 99%) was added at rt under nitrogen atmosphere. The resulting mass was stirred and refluxed (80°C) for 3h. After 3h a sample was taken and submitted for ¹H NMR analysis and show a ratio (DP/SM) 90:10. Reaction Monitoring: An aliquot was concentrated under reduced pressure under inert atmosphere then dissolved in CDCl3 and submitted for ¹H NMR. Work up: Reaction mixture was cooled to rt and let the product crystallised. Crude mass was stirred with THF (50 mL) at RT for 1hr then solid collected by filtration. The solid was triturate with THF( 50 ml) then filtered and then dried at 20 mbar at rt for 1h. Solid is quite hygroscopic. Store under N2. Crude weight: 32g, quant NMR purity- 97%. Chem. Yield 95% NMR data: 1H NMR (400 MHz, CDCl3) δ ppm: 1.24 (t, J=7.15 Hz, 3 H) 3.29 (t, J=6.24 Hz, 2 H) 4.12 (q, J=7.34 Hz, 2 H) 5.39 (t, J=6.24 Hz, 2 H) 8.61 - 8.72 (m, 1 H) 8.97 (ddd, J=8.25, 6.05, 1.83 Hz, 1 H) 9.46 (d, J=5.05 Hz, 1 H) 10.87 (d, J=5.87 Hz, 1 H) LCMS data: 0.80 min, ms esi += 181 [M+H-Br-], (Standard Long method) Example 6: Preparation of ethyl 3-pyridazin-1-ium-1-ylpropanoate 2,2,2-trifluoroacetate

Equipment: A clean and dry 50mL, 3 neck Reaction Flask (RF) fitted with thermometer through pocket, N2 inlet through Schlenk line (pre-fitted with Drierite) septa placed over a magnetic stirrer (500 RPM) Procedure: Pyridazine (2.00 g, 24.5 mmol, 98%,1.81 mL) was weighted directly into the reaction flask. acetonitrile (10 mL/g, 20.0 mL) was added. Trifluoroacetic acid (2.00 equiv., 48.9 mmol, 98.5%, 5.67 g, 3.81 mL) was added via a syringe. Reaction mixture was heated to 95°C (slight turbid solution). Internal temperature attained: 75°C. Ethyl acrylate (1.50 equiv., 36.7 mmol, 98%, 3.75 g, 4.07 mL) was added via syringe over a period of 2.0 min at 75°C. Stirred at 75°C (the slight turbid solution turned light brown). The reaction mixture was heated to 82°C for 20h. Reaction Monitoring: 0.5 ml of the reaction mass was withdrawn via dropper and concentrated to dryness and submitted for 1-HNMR. Workup: Reaction was stopped and cooled to room temp. The reaction mixture was concentrated to dryness. To the reaction mixture water (50 ml) was added and the aqueous layer was washed with TBME (2x50mL). TBME layer discarded. The aqueous layer was lyophilized overnight to remove water. After lypholisation the material was taken in ACN and concentrated. The material was further azerotroped with toluene (2x50mL) and dried in vacuo (rotary evaporator) to remove the residual water present. The desired product ethyl 3-pyridazin-1-ium-1-ylpropanoate;2,2,2-trifluoroacetate (7.20 g, 23.6 mmol, 96.4%) was obtained as thick brown liquid. Isolated Yield: 7.20g, Purity (quant. NMR: 96.4%) Yield: 96.4%. brown liquid. NMR data: 1H NMR (400 MHz, MeOD) δ ppm: 1.24 (t, J=7.15 Hz, 3 H) 3.25 (t, J=6.24 Hz, 2 H) 4.12 (q, J=7.34 Hz, 2 H) 5.15 (t, J=6.24 Hz, 2 H) 8.60 (m, 1 H) 8.65 (ddd, J=8.25, 6.05, 1.83 Hz, 1 H) 9.55 (d, J=5.05 Hz, 1 H) 9.93 (d, J=5.87 Hz, 1 H) LCMS data: 0.15 min, ms esi += 181 [M+H-CF3COO-], (HSS T3 GENERAL 1-6 min method) Example 7: Preparation of ethyl 3-pyridazin-1-ium-1-ylpropanoate tetrafluoroborate

Equipment: A clean and dry 50mL, 3 neck Reaction Flask (RF) fitted with thermometer through pocket, air findenser, N2 inlet through Schlenk line (pre-fitted with Drierite) septa placed over a magnetic stirrer (500 RPM) Procedure: The reaction flask was charged with tetrafluoroboric acid (4.50 g, 25.0 mmol, 48%, 3.25 ml) and cooled to 0°C then pyridazine (2.00 g, 24.5 mmol, 98%,1.81 mL) was added over 5 min to give a homogeneous solution which quickly start to crystallize. The solution was freeze dried then stripped at 0.3 mBar at RT until constant mass to give pale cream solid mass 4.198g, dry and free flow in (nmr in d3ACN showed 95% pure). ethyl acrylate (2.0 equiv., 4.9 g, 50.0 mmol, 98%, 5.35 mL) and acetonitrile (16 mL9 were added and then reaction mixture was heated for 40h (internal temperature 80°C). Reaction Monitoring: 0.05 mL of the reaction mass was diluted in d3ACN and submitted for 1-HNMR. Workup: Reaction worked up by vaccing down at 100 to 0.2mBar at 40°C to give gum which crystallised at RT to a pale beige solid. The desired product ethyl 3-pyridazin-1-ium-1- ylpropanoate;tetrafluoroborate (6.60 g, 23.6 mmol, 96.4%) was obtained as a pale beige solid. Isolated Yield: 6.60g, Purity (quant. NMR: 98%) Yield: 98.6%. NMR data: 1H NMR (400 MHz, DMSO) δ ppm: 1.18 (t, J=7.15 Hz, 3 H) 3.18 (t, J=6.24 Hz, 2 H) 4.08 (q, J=7.34 Hz, 2 H) 5.08 (t, J=6.24 Hz, 2 H) 8.63 (m, 1 H) 8.72 (ddd, J=8.25, 6.05, 1.83 Hz, 1 H) 9.62 (d, J=5.05 Hz, 1 H) 9.97 (d, J=5.87 Hz, 1 H) Example 8: Preparation of methyl 3-pyridazin-1-ium-1-ylpropanoate tetrafluoroborate

Equipment: clean and dry 100mL, 3 neck Reaction Flask (RF) fitted with thermometer through pocket, N2 inlet. Procedure: Pyridazine (5.00 g, 61.18mmol, 98%, 4.533mL) was weighted directly into the reaction flask then HBF4 (45% in water) (1.5 equiv., 91.77 mmol, 45 mass%, 17.91 g, 13 mL) was added via measuring cylinder. Reaction mixture was heated at 95°C (external). A slight turbid solution was obtained. At 75°C, Methyl Acrylate (1.00 equiv., 61.18 mmol, 99%, 5.32 g, 5.6 mL) was added via syringe over a period of 2.0 min. The slight turbid solution turned to a light brown color. The reaction mixture was heated at 75°C for 2.0h. Additional Methyl Acrylate (1.00 equiv., 61.18 mmol, 99%, 5.32 g, 5.6 mL) was added via syringe over a period of 2.0 min at 75°C. The reaction mixture was heated at 75°C for 2.0h. Methyl Acrylate (1.00 equiv., 61.18 mmol, 99%, 5.32g, 5.6 mL) was added a 3^rd time via syringe over a period of 2.0 min at 75°C. The reaction mixture was heated at 75°C for 4h. and kept overnight at 60°C (16h).1HNMR indicated Pyridazine was completely consumed Reaction Monitoring: 0.5 ml of the reaction mass was withdrawn via dropper and concentrated to dryness in rota and submitted for 1-HNMR. NMR showed new peak formation at δ= 9.47 and 9.46 and the peak of Pyridazine appear at δ= 9.23 and 8.23 Workup: The reaction mixture was concentrated to dryness under reduced pressure and submitted for 1HNMR: Desired ester and its corresponding acid were identified (ca.59% of methyl ester 5). The crude mixture was taken up in Toluene: MeOH (7:3) (100 ml) was added then concentrated in vacuo to remove by water azeotropic distillation. This operation was repeated 5x. The crude material obtained was next dissolved in MeOH (90mL) and refluxed for 16h. Full convergence to methyl ester 5 was observed. The reaction mixture was concentrated to dryness. Purification: To the crude reaction mixture was added TBME (50mL). After stirring for 10 min, the TBME layer was decanted and separated. This operation was repeated 2 more times. The resulting material was dried under pressure to furnish methyl 3-pyridazin-1-ium-1-ylpropanoate; tetrafluoroborate as a thick light yellowish liquid (15.7g). Isolated Yield: 15.7g (Purity: 93.6%). Yield: 94.4% NMR data: 1H NMR (400 MHz, MeOD) δ ppm: 3.29 (2 H) 3.69 (3H) 5.18 (2 H) 8.57 - 8.62 (1 H) 8.67 (1 H) 9.58 (1 H) 9.98 (1 H) Example 9: Preparation of methyl 3-pyridazin-1-ium-1-ylpropanoate chloride

Equipment: A clean and dry 50mL, 3 neck Reaction Flask (RF) fitted with thermometer through pocket, N2 inlet through Schlenk line (pre-fitted with Drierite) septa placed over a magnetic stirrer (500 RPM). Procedure: 3-pyridazin-1-ium-1-ylpropanoic acid chloride (1.000 g, 5.037 mmol, 95 mass%) was weighted directly into the reaction flask. Methanol (10 mL/g, 10.0 mL) and DMF (0.005equiv., 0.002mL) was added via measuring cylinder then thionyl chloride (1.50 equiv., 7.55 mmol, 98 mass %, 0.56 mL) was added over a period of 2.0 min via measuring syringe. Reaction mixture was stirred at rt for 2h. Reaction Monitoring. An aliquot was concentrated, dissolved in MeOD and submitted for 1-HNMR Work up. The reaction mass was concentrated to dryness in rota-vap under nitrogen. To the mass 50 ml of TBME added under N2 and stirred for 10 min. The mass became gummy lumps then TBME layer decanted. The gummy once again stirred with 50 ml of TBME added under N2 and stirred for 10 min. Finally, the TBME layer decanted and the solid dried in rota at 48°C to obtain 1.24 g of light brownish gummy mass. Isolated Yield: 1.24 g, (Q-Purity: 79.34%) Yield: 96.4% NMR data: 1H NMR (400 MHz, MeOD) δ ppm: 3.29 (2 H) 3.69 (3H) 5.18 (2 H) 8.57 - 8.62 (1 H) 8.67 (1 H) 9.58 (1 H) 9.98 (1 H) LCMS data: 0.13 min, ms esi += 167 [M+H-Cl-], (HSS T3 GENERAL 1-6 min method) Example 10: Preparation of methyl 3-pyridazin-1-ium-1-ylpropanoate bromide

Equipment: A clean and dry 500mL, 3 neck Reaction Flask (RF) fitted with thermometer through pocket, N2 inlet through Schlenk line (pre-fitted with Drierite) septa placed over a magnetic stirrer (500 RPM). Procedure: Pyridazine (5.0 g, 62 mmol, 98%) was weighted directly into the reaction flask. acetonitrile (10 mL/g, 50.0 mL) was added. Methyl 3-bromopropionate (1.5 equiv., 92 mmol, 98.5%, 15.6 g, 10.2 mL) was added via measuring cylinder. Reaction mixture was heated to 95°C. Internal temperature attained: 82°C. The reaction mixture was heated to 82°C for 6h. Reaction Monitoring. An aliquot was concentrated, dissolved in MeOD and submitted for 1-HNMR. Work up. The reaction mass was concentrated to dryness in rota-vap ubder nitrogen. The crude was then mixed with 80 ml of 3:7 (Two times) Methanol:Toluene mixture and concentrated in rota at 55°C to obtain gummy mass brown colour. To the mass 60 ml of TBME added under N2 and stirred for 10 min. The mass became solid lumps, it was then broke into small particle and the TBME layer decanted. The solid once again stirred with 60 ml of TBME added under N2 and stirred for 10 min. Finally, the TBME layer decanted and the solid dried in rota at 48°C to obtain 6.26 g of light brownish free flowing sold (very much hygroscopic). Isolated Yield: 15.05 g, (Q-Purity: 98.95%) Yield: 95.51 NMR data: 1H NMR (400 MHz, MeOD) δ ppm: 3.29 (2 H) 3.69 (3H) 5.18 (2 H) 8.57 - 8.62 (1 H) 8.67 (1 H) 9.58 (1 H) 9.98 (1 H) LCMS data: 0.13 min, ms esi += 167 [M+H-Br-], (HSS T3 GENERAL 1-6 min method) Example 11: Preparation of methyl 3-pyridazin-1-ium-1-ylpropanoate bromide 2,2,2- trifluoroacetate

Equipment: A clean and dry 50mL, 3 neck Reaction Flask (RF) fitted with thermometer through pocket, N2 inlet through Schlenk line (pre-fitted with Drierite) septa placed over a magnetic stirrer (500 RPM). Procedure: Pyridazine (1.0 g, 12 mmol, 94%) was weighted directly into the flushed reaction flask. acetonitrile (10 mL/g, 10.0 mL) was added. Methyl prop-2-enoate (1.50 equiv., 18 mmol, 99%, 1.5 g, 1.62 mL) was added via measuring syringe followed by addition of trifluoroacetic acid (2.00 equiv., 23.6 mmol, 99 mass%, 2.7 g, 1.83 g). Reaction mixture was heated to 95°C. Internal temperature attained: 80°C. The reaction mixture was heated to 80°C. Reaction Monitoring. Aliquot was diluted in Methanol and submitted for Agilent HPLC at 240nm Work up. The reaction mass was concentrated and 10mL/g TBME was added and triturate for 1hr. It was then concentrated and stripped up with toluene. Crude Yield: 4.51 g, (Q-Purity: 69.2%) Yield: 94% NMR data: 1H NMR (400 MHz, MeOD) δ ppm: 3.33 (2 H) 3.70 (3H) 5.25 (2 H) 8.60 (1 H) 8.73 (1 H) 9.61 (1 H) 10.00 (1 H) Example 12: Preparation of 3-pyridazin-1-ium-1-ylpropanoic acid chloride –

Equipment: a 250mL 3 neck RBF along with a reflux condenser and a N2 inlet. Procedure: Pyridazine (10 g, 118.1 mmol, 94.6%) was added at 24°C followed by ACETONITRILE (3.06 mL/g) was added. To the homogeneous solution is added 3-chloropropanoic acid (1.2 equiv., 141.8 mmol, 100%) at 24°C. The reaction mixture was heated to 80°C. The mixture became black after 30min. After 15h at 82°C NMR indicated 35% of SM and 65% of DP Reaction Monitoring: An aliquot was concentrated, dissolved in MeOD and submitted for NMR analysis and NMR ratio was determinate. Work up: Reaction mass was cooled at RT. It was filtered and washed with Acetonitrile (10 Vol). The solid bed was washed with 7.5V TBME (7.5 vol). The solid was then concentrated under reduced pressure and submitted for Quant. NMR. Crude dark brown oil obtained: 17.46g, QNMR purity 96.85%. Chem. Yield 75.9% NMR data: 1H NMR (400 MHz, DMSO) δ ppm: 3.25 (t, J=6.19 Hz, 2 H) 4.92 (br s, 1 H) 5.14 (t, J=6.11 Hz, 2 H) 8.57 - 8.62 (m, 1 H) 8.67 (t, J=6.64 Hz, 1 H) 9.58 (br d, J=4.12 Hz, 1 H) 9.97 (d, J=5.87 Hz, 1 H) Example 13: Preparation of 3-pyridazin-1-ium-1-ylpropanoic acid bromide

Equipment: 50mL 3 neck RBF along with a reflux condenser and N2 inlet. Procedure: Pyridazine (1 g, 12 mmol, 98%) was added at rt followed by acetonitrile (10mL) was added. To the homogeneous solution is added 3-bromopropanoic acid (1.2 equiv., 14.8 mmol, 100%, 2.3 g) at 24°C. The reaction mixture was heated to 80°C. The mixture became black after 30min. After 6h at 80°C LCMS indicated 4% of SM and 96% of DP. Reaction Monitoring: 0.04 mL aliquot was taken by syringe, RM was diluted by the addition of water (0.9 ml) and submitted for HPLC and LCMS. Work up: Reaction mixture was filter through sintered funnel and washed with MeCN (20 mL) to get off white solid residue (2.44g). (Sample was submitted to Q-NMR, LCMS and HPLC) Crude yield: 2.44 g, QNMR purity 96.6%. Chem. Yield 81.3% NMR data: 1H NMR (400 MHz, D2O) δ ppm: 2.91 - 2.99 (m, 2H) 3.50 - 3.63 (m, 2H) 5.04 - 5.11 (m, 2 H) 8.44 - 8.51 (m, 1 H) 8.51 - 8.58 (m, 1 H) 9.41 - 9.50 (m, 1H) 9.70 - 9.78 (m, 1H) LCMS data: 0.14 min, ms esi += 153 [M+H-Br-], (HSS T3 GENERAL 1-6 min method) Example 14: Preparation of 3-pyridazin-1-ium-1-ylpropanoic acid 2,2,2-trifluoroacetate

Equipment: 50mL 3 neck RBF along with a reflux condenser and N2 inlet. Procedure: In 50 mL three neck RBF 3-pyridazin-1-ium-1-ylpropanoic acid; chloride (0.500 g, 2.60 mmol, 98 mass%) was added followed by ethanol (10.00 mL/g) and stirred for 5 min then the reaction mixture was cooled to 0-5°C.40% Aqueous tetrafluoroboric acid (1.00 equiv., 2.60 mmol, 40 mass%) was added drop wise maintaining temperature below 5°C and then the reaction mixture was stirred at 0-5°C and then allowed to warm to 24°C. After 2h 1-HNMR showed proton in the aromatic region shifted downfield as compare to SM and also 19FNMR showed shift as compare to HBF4, this clearly indicates that there is exchange of chlorine ion with BF4-. Reaction Monitoring: Aliquot was taken out (~0.5 mL) and concentrated on rotary evaporator to afforded residue. Residue was diluted with MeOD and submitted for 1HNMR Work up: Reaction mixture containing ethanol was evaporated on rotary evaporator under reduced pressure (P = 50-0 mbar, T bath = 45-50°C). Crude yield: after concentration = 0.810 g NMR data: 1H NMR (400 MHz, MeOD) δ ppm: 3.15 (m, 2H) 5.04 (m, 2 H) 8.46 (m, 1 H) 8.51 (m, 1 H) 9.45 (m, 1H) 9.78 (m, 1H) Example 15: Preparation of 3-pyridazin-1-ium-1-ylpropanenitrile bromide

Equipment: 50mL 3 neck RBF along with a reflux condenser and N2 inlet. Procedure: In 50 mL three neck RBF 3-pyridazine (4.48 g, 54.4 mmol, 98 mass%) was added followed by toluene (20.00 mL) then the reaction mixture was heated to 80°C.3-Bromopropionitrile (1.1 equiv., 7.090 g, 58.53 mmol, 98 mass%) was added drop wise maintaining temperature below 80°C and then the reaction mixture was stirred at 80°C. After 12h 1-HNMR showed Evidence of DP but still quite a bit of both SM therein. Reaction Monitoring: Aliquot was taken out (~0.1 mL) and concentrated on rotary evaporator to afforded residue. Residue was diluted with DMSO and submitted for 1-HNMR Work up: Reaction mixture Reaction mixture cooled to RT and concentrated in vacuo to give the crude 3-pyridazin-1-ium-1-ylpropanenitrile; bromide (12.4 g, 58.2 mmol) Purification: The residue was taken up in DCM, adsorbed onto isolute and purified on the CombiFlash® (CH2Cl2:MeOH as eluant). Pure fractions combined and concentrated in vacuo to give 3-pyridazin-1-ium-1-ylpropanenitrile; bromide (8.0 g) as a viscous red oil. Pure yield: 8.0 g, QNMR purity 97%. Pure Yield 66% NMR data: 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.04 (br d, 1 H), 9.63 - 9.79 (m, 1 H), 8.82 (ddd, 1 H), 8.63 - 8.75 (m, 1 H), 5.16 (t, 3 H), 3.40 (t, 2 H) LCMS data: 0.61 min, ms esi += 134 [M+H-Br-], (Standard long method) Example 16: One pot Preparation of ethyl 3-[4-(2-pyridyl)pyridazin-1-ium-1-yl]propanoate bromide

Step 1: To a three neck reaction flask, ethyl 3-pyridazin-1-ium-1-ylpropanoate bromide (200 mg, 0.73 mmol) and Copper (I) iodide (10 mol%, 20 mg) was added THF (7.00 mL) and then the reaction mass was cooled to -50 °C, then bromo(2-pyridyl)zinc (0.5 M in THF) (1.20 equiv., 0.87 mmol, 1.75 mL) was added at -50 °C and then stirred for 40 min at this temperature. The reaction mass was stirred for 12h at rt under nitrogen. Intermediate not isolated. LCMS data: 1.20 min, ms esi+=259.9 (GENERAL 2-5 min) Step 2: After 12 h, 0.5 equivalent of DDQ was added and stirred for another 3 h. Work up: Reaction mass was concentrated, and gummy mass was obtained. Crude was washed with TBME (2 x 20ml). Then 50 ml of acetone was added into the crude and stirred for 10 min at rt and then filtered. The filtrate was concentrated to give crude mass (300 mg) and LCMS and 1H NMR of this fraction shows major as desired mass along with impurity coming from DDQ. Sample of crude was dissolved in D2O and NMR was compared with authentic data and confirms the formation of 1,4 addition product. LCMS data: 0.307 min, ms esi+=257.9 (GENERAL 2-5 min)

Claims

CLAIMS: 1. A process for the preparation of a compound of formula (I) or an agronomically acceptable salt or zwitterionic species thereof:

wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I), p is 0, 1 or 2; and R¹ is hydrogen or methyl; R² is hydrogen or methyl; Q is (CR^1aR^2b)m; m is 0, 1 or 2; each R^1a and R^2b are independently selected from the group consisting of hydrogen, methyl, – OH and –NH2; Z is selected from the group consisting of –CN, -CH₂OR³, -CH(OR⁴)(OR^4a), - C(OR⁴)(OR^4a)(OR^4b), –C(O)OR¹⁰, -C(O)NR⁶R⁷ and -S(O)₂OR¹⁰; or Z is selected from the group consisting of a group of formula Za, Zb, Zc, Zd, Ze and Zf below

wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I); and R³ is hydrogen or -C(O)OR^10a; each R⁴, R^4a and R^4b are independently selected from C₁-C₆alkyl; each R⁵, R^5a, R^5b, R^5c, R^5d, R^5e, R^5f, R^5g and R^5h are independently selected from hydrogen and C₁-C₆alkyl; each R⁶ and R⁷ are independently selected from hydrogen and C₁-C₆alkyl; each R⁸ is independently selected from the group consisting of halo, -NH2, methyl and methoxy; R¹⁰ is selected from the group consisting of hydrogen, C₁-C₆alkyl, phenyl and benzyl; and R^10a is selected from the group consisting of hydrogen, C₁-C₆alkyl, phenyl and benzyl; said process comprising the steps: (a) Reacting a compound of formula (II)

wherein A, R¹, R², Q and Z are as defined above.

2. A process according to claim 1, wherein R¹ and R² are hydrogen and R^1a and R^2b are hydrogen.

3. A process according to claim 1 or 2, wherein m is 1 and p is 0.

4. A process according to any one of claims 1 to 3, wherein A is selected from the group consisting of formula A-Ia to A-IIIa below,

wherein the jagged line defines the point of attachment to the remaining part of a compound of formula (I).

5. A process according to any one of claims 1 to 4, wherein Z is selected from the group consisting of –CN, -CH₂OH, –C(O)OR¹⁰ and -S(O)₂OR¹⁰.

6. A process according to any one of claims 1 to 5, wherein Z is –CN or -C(O)OCH₂CH₃.

7. A process according to any one of claims 1 to 6, wherein M¹ is Zn.

8. A process according to any one of claims 1 to 7, wherein the suitable additive is a lewis acid.

9. A process according to any one of claims 1 to 8, wherein the suitable additive is selected from the group consisting of BF3.OEt, MgBr2, ZnBr2, ZnCl2, Zn(OTf)₂ and AlCl3.

10. A process according to any one of claims 1 to 9, wherein the metal amide base is a metal tetramethylpiperidine (TMP) base.

11. A process according to any one of claims 1 to 10, wherein the metal amide base is TMPZnCl.LiCl or TMPZnBr.LiBr.

12. A process according to any one of claims 1 to 11, wherein step (b) is carried out in the presence of a copper catalyst.

13. A process according to claim 12, wherein the copper catalyst is copper (I) iodide or copper (I) cyanide.

14. A process according to any one of claims 1 to 13 wherein the compound of formula (I) is further subjected to a hydrolysis, oxidation and/or a salt exchange to give an agronomically acceptable salt of formula (Ia) or a zwitterion of formula (Ib),

wherein Y¹ is Cl- and j and k are 1, and A, R¹, R² and Q are as defined in any of claims 1 to 6, and Z² is -C(O)OH or -S(O)₂OH.

15. A compound of formula (V)

wherein A, Q, Z, R¹ and R² are as defined in any one of claims 1 to 6.