WO2021234082A1

WO2021234082A1 - Chemical process

Info

Publication number: WO2021234082A1
Application number: PCT/EP2021/063456
Authority: WO
Inventors: Timothy Robert Desson; Simon GRASSL; Paul Knochel; James Nicholas Scutt
Original assignee: Syngenta Crop Protection Ag
Priority date: 2020-05-21
Filing date: 2021-05-20
Publication date: 2021-11-25
Also published as: GB202007594D0

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. 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-l 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)₂0R¹⁰; or

Z is selected from the group consisting of a group of formula Z_a, Z_b, Z_c, Z_d, Z_e and Z_f 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, R⁵⁹ 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)

A— Y

(ii) wherein A is as defined above and Y is selected from the group consisting of chloro, bromo, iodo and - OS(O)₂CF₃, with

(i) an organometallic reagent comprising a metal M¹ and optionally in the presence of at least one or more metal salts, or

(ii) in the presence of elemental metal M¹ and in the presence of at least one or more metal salts, and

M¹ is independently selected from the group consisting of Li, Mg, Mn, Zn and In;

(b) 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 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)

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 Ci- 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 (l-l), or as an agronomically acceptable salt, a compound of formula (l-ll) 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 (l-lll) 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 (l-l) or (l-ll). For compounds of formula (l-ll) 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 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 (l-la) 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 (l-lb) 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 (l-lc) as shown below:

The following list provides definitions, including preferred definitions, for substituents m, n, o, q, A, M¹,

M², Q, Y, 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, R⁵⁹, 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.

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-l, A-ll, A-lll, 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-la, A- I la , A- Ilia, A-IVa, A-Va and A-Vlla below

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- la, A-lla, A-llla and A-Vlla below

(I)·

Even more preferably still, A is a 6-membered heteroaryl selected from the group consisting of formula A-la, A-llla and A-Vlla below

Yet even more preferably still, A is the group A-la or A-llla. Most preferably, A is the group A-la.

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)₂0R¹⁰. Preferably, Z is selected from the group consisting of -CN, - CH2OR³, -C(O)OR¹⁰, -C(O)NR⁶R⁷ and -S(O)₂0R¹⁰. More preferably, Z is selected from the group consisting of-CN, -CH2OH, -C(O)OR¹⁰, -C(O)NH₂ and -S(O)₂0R¹⁰. Even more preferably, Z is selected from the group consisting of -CN, -CH2OH, -C(O)OR¹⁰ and -S(O)₂0R¹⁰. Yet even more preferably still, Z is selected from the group consisting of -CN, -C(O)OR¹⁰ and -S(O)₂0R¹⁰. Yet even more preferably still, Z is selected from the group consisting of -CN, -C(O)OCH2CH3, -C(O)OCC(CH3)3, -C(O)OH and - S(O)₂0H. 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.

In an alternative embodiment Z is selected from the group consisting of a group of formula Z_a, Zb, Z_c, Zd, Z_e and Z_f 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 Z_a, Z_b, Zd, Z_e and Z_f. More preferably, Z is selected from the group consisting of a group of formula Z_a, Zd and Z_e.

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)₂0R¹⁰, or Z is selected from the group consisting of a group of formula Z_a, Zd and Z_e. Preferably, Z is selected from the group consisting of -CN, -CH2OH, -C(O)OR¹⁰, -S(O)₂0R¹⁰ 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, R⁵⁹ 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, R⁵⁹ 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, R⁵⁹ 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, R^10a 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-buty.l Preferably, R¹⁰ is ethyl.

Y is selected from the group consisting of chloro, bromo, iodo and -OS(O)₂CF₃. Preferably, Y is selected from the group consisting of chloro, bromo and iodo.

In one embodiment Y is chloro.

In another embodiment Y is bromo.

In another embodiment Y is iodo.

M¹ is independently selected from the group consisting of Li (Lithium), Mg (Magnesium), Mn (Manganese), Zn (Zinc) and In (Indium). Preferably M¹ is independently selected from the group consisting of Li, Mg and Zn. More preferably, M¹ is Mg or Zn.

In one embodiment M¹ is Mg.

In another embodiment 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 (la) or a zwitterion of formula (lb),

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 CI 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 (la),

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 CI- 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 (la) 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 (la) Y¹ is Cf 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-la, A-lla, A-llla and A- VI la 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-la or A- Ilia);

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, -S(O)₂OR¹⁰ and -CH=CH2; 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-l), (V-ll), (V-lll), (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, /so-propyl, 2,2-dimethylpropyl and tert-b)u.tyl 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-Vla), (V-Vlb) and (V-Vlc) below (preferably, V-Va or V-Vla)

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, -S(O)₂OR¹⁰ and -CH=CH2; 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-llla) or (IV-lllb) 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:

Suitable agronomically acceptable salts for a compound of formula (IV), represented by an anion Y¹, 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-fl), (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.

The skilled person would envisage that structures such as a compound of formula (III) could be formed from the reaction conditions described in either process step (a) (i) or step (a) (ii) 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, Mg, Mn, Zn and In.

X¹ is independently selected from the group consisting of F, Cl, Br, I, CN, SCN, NCO, CIO3, CIO₄, BrO₃, BrO₄, NO₃, BF₄, PF₆, R^aCO₂, OR^b and R^CSO₃. Preferably, X¹ is independently selected from the group consisting of F, Cl, Br, I, CN, CIO₃, CIO₄, BrO₃, BrO₄, R^aCO₂, OR^b and R^CSO₃. 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, CIO₃, CIO₄, 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, CIO₃, CIO₄, 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-la, A-llla and A-Vlla 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;

X¹ is independently selected from the group consisting of F, Cl, Br, I, CN, SCN, NCO, CIO3, CIO4, BrC>3, BrO₄, NO₃, BF₄, PF₆, R^aCO₂, OR^b and R^CSO₃ (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, CIO3, CIO4, BrC>3, BrC>4, R^aCC>2, 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;

0 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 (lll-i), (lll-ii), (lll-iii), (lll-iv), (lll-v), (lll-vi), (lll-vii), (lll-viii), (lll-ix), (lll-x), (lll-xi) and (lll-xii) below,

Wherein X¹ is independently selected from the group consisting of F, Cl, Br, I, CN, SCN, NCO, CIO3, CIO₄, BrO₃, BrO₄, NO₃, BF₄, PF₆, R^aCO₂, OR^b and R^CSO₃ (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 (lll-b), (lll-c), (lll-d), (lll-e), (lll-f), (lll-g), (lll-h) and (lll-j) below,

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

Step ( a) (i):

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

wherein A and Y are as defined herein, with an organometallic reagent comprising a metal M¹ and optionally in the presence of at least one or more metal salts, wherein M¹ is as defined herein.

Typically in this process of the invention such organometallic reagents contain a metal for example in a covalent bond or a complex such as metal-alkyl- or metal-aryl- compounds. Preferably in the process of the invention the organometallic reagent is an organozinc or an organomagnesium reagent. More preferably, the organometallic reagents is an alkylzinc or an alkylmagnesium reagent. Even more preferably, the organometallic reagents is selected from the group consisting of isopropylmagnesium bromide, isopropylmagnesium bromide. lithium chloride, isopropylmagnesium chloride, isopropylmagnesium chloride. lithium chloride, sec-butylmagnesium chloride, di-sec-butylmagnesium chloride, sec-butylmagnesium chloride. lithium chloride, di-sec-butylmagnesium. lithium chloride, tert- butylmagnesium chloride, n-butylmagnesium chloride and ethylmagnesium chloride. Even more preferably still, the organometallic reagents is isopropylmagnesium chloride or isopropylmagnesium chloride. lithium chloride.

Preferably in the process of the invention this step is carried out in the presence of at least one or more metal salts, such as, but not limited to, magnesium chloride, magnesium bromide, zinc bromide, zinc chloride, zinc trifluoromethanesulfonate, zinc acetate, zinc pivalate and lithium chloride. More preferably, the metal salt is selected from the group consisting of lithium chloride, magnesium chloride and magnesium bromide. Even more preferably, the metal salt is lithium chloride.

Typically the process described in step (a) (i) 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 can be carried out at a temperature of from -78 °C to 120 °C, preferably, from -20 °C to 60 °C. More preferably, from -20 °C to 20 °C. Even more preferably, from -20 °C to 0 °C.

Preferably process step (a) (i) of the present invention is carried out under an inert atmosphere, such as nitrogen or argon.

Step (a) (ii):

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

wherein A and Y are as defined herein, with in the presence of elemental metal M¹ and in the presence of at least one or more metal salts, wherein M¹ is as defined herein.

The elemental metal (M¹) used in the process of the invention can be activated priorto use in the process by known methods in the art. One method of activation is to produce a finely divided metal from a chemical reaction (for example Rieke metal produced by reduction of a metal salt with an alkali metal), or an alternative method is by adding known reagents to remove any unreactive surface layer, such as, but not limited to 1 ,2-dibromoethane, bromine, iodine, vitride (sodium bis(2-methoxyethoxy)aluminium hydride), DIBAL-H (diisobutylaluminium hydride), lithium chloride, magnesium bromide, or pre-washing with a mineral acid. The skilled person would also appreciate that a heel of a previous reaction could be used to activate the elemental metal (M¹).

Preferably, the elemental metal (M¹) 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, the elemental metal (M¹) is used in an amount of from 2 to 4 equivalents, relative to the number of moles of the compound of formula (II).

The skilled person would appreciate that the metal salt (preferably, metal halide) used in the process can facilitate the conversion of a compound of formula (II). The metal salt (preferably, metal halide) may be used in stoichiometric or sub-stoichiometric or catalytic amounts.

Preferably in the process of the invention this step is carried out in the presence of at least one or more metal salts selected from the group consisting of a cobalt salt, a nickel salt, a magnesium salt, a zinc salt and a lithium salt. More preferably, in the process of the invention this step is carried out in the presence of at least one or more metal salts selected from the group consisting of cobalt (II) chloride, cobalt (II) bromide, cobalt (II) nitrate, cobalt (II) sulfate, cobalt (II) acetate, cobalt (II) pivalate, magnesium chloride, magnesium bromide, zinc bromide, zinc chloride, zinc trifluoromethanesulfonate, zinc acetate, zinc pivalate and lithium chloride. Even more preferably, in the process of the invention this step is carried out in the presence of at least one or more metal salts selected from the group consisting of cobalt (II) chloride, cobalt (II) bromide, zinc bromide, zinc chloride, zinc trifluoromethanesulfonate, zinc acetate, zinc pivalate and lithium chloride. Even more preferably still, in the process of the invention this step is carried out in the presence of at least one or more metal salts selected from the group consisting of cobalt (II) chloride, zinc chloride, zinc pivalate and lithium chloride. Yet even more preferably still, in the process of the invention this step is carried out in the presence of at least one or more metal salts selected from the group consisting of cobalt (II) chloride, zinc chloride and zinc pivalate.

In a preferred embodiment, this step is carried out in the presence of at least two or more metal salts selected from the group consisting of a cobalt salt, a nickel salt, a magnesium salt, a zinc salt and a lithium salt. Preferably, this step is carried out in the presence of at least two metal salts selected from the group consisting of cobalt (II) chloride, cobalt (II) bromide, cobalt (II) nitrate, cobalt (II) sulfate, cobalt (II) acetate, magnesium chloride, magnesium bromide, zinc bromide, zinc chloride, zinc trifluoromethanesulfonate, zinc acetate, zinc pivalate and lithium chloride. More preferably, in the process of the invention this step is carried out in the presence of at least two or more metal salts selected from the group consisting of cobalt (II) chloride, cobalt (II) bromide, zinc bromide, zinc chloride, zinc trifluoromethanesulfonate, zinc acetate, zinc pivalate and lithium chloride. Even more preferably, in the process of the invention this step is carried out in the presence of at least two or more metal salts selected from the group consisting of cobalt (II) chloride, zinc chloride, zinc pivalate and lithium chloride. Even more preferably still, in the process of the invention this step is carried out in the presence of at least two or more metal salts selected from the group consisting of cobalt (II) chloride, zinc chloride and zinc pivalate. Most preferably, in the process of the invention this step is carried out in the presence of cobalt (II) chloride and zinc pivalate.

Typically when the metal salt is selected from a cobalt salt or a nickel salt, it is used in sub-stoichiometric or catalytic amounts. Preferably, from 0.1 mol% to 50 mol% (based on a compound of formula (II)). More preferably, from 1 mol% to 20 mol%, even more preferably from 5 mol% to 15 mol%.

Typically when the metal salt is selected from a a magnesium salt, a zinc salt or a lithium salt, it is used in stoichiometric amounts, sub- stoichiometric amounts or in excess (preferably, in a molar ratio, relative to the number of moles of the compound of formula (II), of from 0.5 to 3.0).

In an even more preferred embodiment, this step is carried out in the presence of cobalt (II) chloride (preferably, from 0.1 mol% to 50 mol%, more preferably from 1 mol% to 20 mol%) and zinc chloride or zinc pivalate.

In one embodiment, this step is carried out in the presence of elemental Zn and a cobalt salt (preferably, from 0.1 mol% to 50 mol%, more preferably from 1 mol% to 20 mol%) and a zinc salt (preferably, in a molar ratio, relative to the number of moles of the compound of formula (II), of from 0.5 to 3.0). Preferably, this step is carried out in the presence of elemental Zn and cobalt (II) chloride (preferably, from 0.1 mol% to 50 mol%, more preferably from 1 mol% to 20 mol%) and zinc chloride or zinc pivalate (preferably, in an amount of from 0.5 to 3 equivalents, relative to the number of moles of the compound of formula (II)).

In another embodiment, this step is carried out in the presence of elemental Zn and a cobalt salt and a zinc salt, wherein the proportion of cobalt salt to zinc salt is from 1 :2 to 1 :100 (preferably from 1 :3 to 1 :50, more preferably from 1 :3 to 1 :20).

Typically the process described in step (a) (ii) 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.

In a preferred embodiment, step (a) (ii) is carried out in a solvent, or mixture of solvents selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, benzonitrile, benzyl cyanide, 1 ,2-dicyanobenzene (phthalonitrile), 1 ,4-dicyanobenzene, 4-(Trifluoromethyl)benzonitrile, 4- Methoxybenzonitrile, 4-Methylbenzonitrile, 2-Furonitrile and 2-Thiophenecarbonitrile. Preferably, step (a) (ii) is carried out in a solvent, or mixture of solvents selected from the group consisting of acetonitrile, benzonitrile, benzyl cyanide, 1 ,2-dicyanobenzene (phthalonitrile), 1 ,4-dicyanobenzene, 4- (Trifluoromethyl)benzonitrile, 4-Methoxybenzonitrile, 4-Methylbenzonitrile, 2-Furonitrile and 2- Thiophenecarbonitrile. More preferably, step (a) (ii) is carried out in a solvent, or mixture of solvents selected from the group consisting of benzonitrile, 1 ,4-dicyanobenzene, 4-Methoxybenzonitrile and 4- Methylbenzonitrile. Most preferably, step (a) (ii) is carried out in benzonitrile.

This step can be carried out at a temperature of from -78 °C to 120 °C, preferably, from -20 °C to 60 °C. More preferably, from -20 °C to 30 °C. Even more preferably, from 0 °C to 30 °C.

Preferably process step (a) (ii) of the present invention is carried out under an inert atmosphere, such as nitrogen or argon.

Step (b) Nucleophilic Addition:

Compounds of formula (V) can be produced by reacting the product of step (a) (i) or step (a) (ii), 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) (i) or step (a) (ii) 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) (i) or step (a) (ii) (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 °C to 120 °C, 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:

TiCI, 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 (NalO4, 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), NaOCI (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 (DDQ), 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, alcohols (such as MeOH, iPrOH, EtOH, BuOH, tBuOH, tert amyl alcohol), tetrahydrofuran, 2-methyltetrahydrofuran, diethylether, tert-butymlethylether, tert-amyl methyl ether, cyclopentyl methyl ether, dimethoxymethane, diethoxymethane, dipropoxy methane, 1 ,3-dioxolane, ethyl acetate, dimethyl carbonate, dichloromethane, dichloroethane, A/,A/-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) (i) or (ii), (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 (la) or a zwitterion of formula (lb),

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 CI 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)₂0H (the skilled person would appreciate that Z^2_ represents -C(O)O^_ or - S(O)₂O ).

Scheme 2:

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 °C to 120 °C (preferably, from 20 °C to 100 °C).

Step (q) Salt Exchange:

The salt exchange of a compound of formula (I) to a compound of formula (la) 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 (la) 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 (la) is performed with barium chloride.

In a preferred embodiment of the invention there is provided a process forthe 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-la to A- IIIa (preferably A- la or A-llla, more preferably A-la) below

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)

wherein A is as defined above and Y is iodo, with

(i) isopropylmagnesium chloride or isopropylmagnesium chloride. lithium chloride,

(b) reacting the product of step (a) (i) 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.

In another 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 selected from the group consisting of formula A-la to A- Ilia (preferably A- la or A-llla, more preferably A-la) below

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)

wherein A is as defined above and Y is chloro or bromo (preferably chloro),

(ii) in the presence of elemental Zn and Cobalt (II) chloride (preferably present in catalytic amounts, more preferably, from 0.1 mol% to 50 mol% (based on a compound of formula (II)), even more preferably, from 1 mol% to 20 mol%) and Zinc chloride or Zinc Pivalate, and

(b) reacting the product of step (a) (ii) 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.

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, T, = 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 pm, 30 x2.1 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 pm, 30 x2.1 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 Ή' 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 pm 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: Preparation of pyrimidin-2-ylmagnesium chloride. lithium chloride and 2- deuteriopyrimidine

A mixture of 2-iodopyrimidine (0.1 g, 0.48 mmol) and internal standard para-tolyl ether (0.044 g, 0.22 mmol) were dissolved in anhydrous tetrahydrofuran (1 mL). The solution was purged with nitrogen, evacuated, and this process was repeated three times. The solution was cooled to -15°C and isopropylmagnesium chloride lithium chloride solution (1.3M solution in tetrahydrofuran, 0.39 mL, 0.51 mmol) was added drop wise over 2 minutes. After stirring at this temperature for 10 minutes an aliquot was removed and quenched into methanol-d₄ (0.6 ml_) to confirm a 95% yield of 2-deuteriopyrimidine (by reference to the ¹H NMR internal standard) as evidence of pyrimidin-2-ylmagnesium chloride formation.

¹H NMR (400 MHz, CD₃OD) 8.80 (d, 2H), 7.55 (t, 1 H)

Example 2: Preparation of pyridazin-3-ylmagnesium chloride. lithium chloride and 3- deuteriopyridazine

A mixture of 3-iodopyridazine (0.1 g, 0.49 mmol) and internal standard para-tolyl ether (0.048 g, 0.24 mmol) were dissolved in anhydrous tetrahydrofuran (1 mL ). The solution was purged with nitrogen, evacuated, and this process was repeated three times. The solution was cooled to -10°C and isopropylmagnesium chloride lithium chloride solution (1.3M solution in tetrahydrofuran, 0.41 mL , 0.53 mmol) was added drop wise over 1 minute. After stirring at this temperature for 10 minutes an aliquot was removed and quenched into a mixture of acetic acid-d₄ (0.15 mL ) and dimethyl sulfoxide-d6 (0.5 mL ) to confirm a 98% yield of 3-deuteriopyridazine (by reference to the ¹H NMR internal standard) as evidence of pyridazin-3-ylmagnesium chloride formation.

¹H NMR (400 MHz, CD₃CO₂D/DMSO-d₆) 9.14 (t, 1 H), 7.61 (d, 2H)

Example 3: Preparation of ethyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate chloride

Step 1 : 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, 1 H), 9.43-9.56 (m, 1 H), 8.43-8.69 (m, 2H), 5.15 (t, 2H), 4.11 (q, 2H), 3.27 (t, 2H), 1.16 (t, 3H)

Step 2: Preparation of pyrimidin-2-ylmagnesium chloride. lithium chloride

A solution of 2-iodopyrimidine (0.59 g, 2.87 mmol) in anhydrous tetrahydrofuran (6 mL ) was purged with nitrogen, evacuated, and this process was repeated three times. After cooling to -15°C a solution of isopropylmagnesium chloride lithium chloride (1.3M solution in tetrahydrofuran, 2.31 ml, 3.01 mmol) was added drop wise over 10 minutes and the reaction mixture was stirred at this temperature for a further 15 minutes to afford a solution of pyrimidin-2-ylmagnesium chloride.

Step 3: Preparation of ethyl 3-(4-pyrimidin-2-yl-4H-pyridazin-1-yl)propanoate

In a separate flask a mixture of ethyl 3-pyridazin-1-ium-1-ylpropanoate bromide (0.5 g, 1 .91 mmol), copper(l) iodide (0.037 g, 0.191 mmol) and internal standard para-tolyl ether (0.19 g, 0.96 mmol) was purged with nitrogen, evacuated, and this process was repeated three times. Anhydrous tetrahydrofuran (6 mL ) was added and the resulting suspension was cooled to -10°C. To this mixture was added the pre-formed pyrimidin-2-ylmagnesium chloride solution drop wise over 2 hours 45 minutes. An aliquot was removed from the reaction mixture and quenched into a mixture of acetic acid-d₄ (0.16 mL ) and dimethyl sulfoxide-d6 (0.5 mL ) to confirm a 65% yield of ethyl 3-(4-pyrimidin-2-yl- 4H-pyridazin-1-yl)propanoate (by reference to the ¹H NMR internal standard). This crude solution was used directly in the next step.

¹H NMR (600 MHz, CD₃CO₂D/DMSO-d₆) 8.68 (d, 2H), 7.27 (t, 1 H), 6.60 (t, 1 H), 6.29 (d, 1 H), 4.68 (ddd, 1 H), 4.16 (t, 1 H), 3.99 (q, 2H), 3.54 (m, 2H), 2.51 (t, 2H), 1.11 (t, 3H)

Step 4: Preparation of ethyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate chloride

To the crude solution of ethyl 3-(4-pyrimidin-2-yl-4H-pyridazin-1-yl)propanoate was added N- chlorophthalimide (0.452 g) in one portion at -10°C. The resulting suspension was stirred at this temperature for 30 minutes, then for an additional 15 hours at 3°C. An aliquot of the reaction mixture was quenched into a mixture of acetic acid-d₄ (0.16 mL ) and dimethyl sulfoxide-d6 (0.5 mL ) to confirm a 50% yield of ethyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate chloride (by reference to the ¹H NMR internal standard). The remaining reaction mixture was quenched with 2M aqueous hydrochloric acid (5 mL ). After diluting with additional water (6 mL ) the reaction mixture was partially concentrated to remove organic solvents then washed with ethyl acetate (20 mL ). Half of the aqueous solution was used directly in the next step and the remainder was freeze dried to afford crude ethyl 3-(4-pyrimidin- 2-ylpyridazin-1-ium-1-yl)propanoate chloride as a tacky brown solid. ¹H NMR (400 MHz, D₂O) 10.16 (d, 1 H), 9.86 (d, 1 H), 9.18 (dd, 1 H), 8.99 (d, 2H), 7.64 (t, 1 H), 5.13 (t, 2H), 4.06 (q, 2H), 3.25 (t, 2H), 1 .11 (t, 3H)

Example 4: Preparation of 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride

The crude ethyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate chloride solution was acidified to below pH 1 with 2M aqueous hydrochloric acid, heated for 15 hours at 45°C, then for a further 90 minutes at 60°C. Additional 5.9M aqueous hydrochloric acid (1 ml_) was added and heating was continued for an additional hour. After cooling to room temperature the reaction mixture was freeze dried to afford 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoic acid chloride as a tacky brown solid.

¹H NMR (400 MHz, D₂O) 10.16 (d, 1 H), 9.86 (d, 1 H), 9.21-9.15 (m, 1 H), 8.99 (d, 2H), 7.64 (t, 1 H), 5.11 (t, 2H), 3.24 (t, 2H) (CO₂H proton missing)

Example 5: Preparation of ethyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate salt via in situ oxidation

Wherein X- is an undefined salt.

Step 1 : Preparation of pyrimidin-2-ylmagnesium chloride. lithium chloride

A solution of 2-iodopyrimidine (0.2 g, 0.97 mmol) in anhydrous tetrahydrofuran (2.2 mL ) was purged with nitrogen, evacuated, and this process was repeated three times. After cooling to -15°C a solution of isopropylmagnesium chloride lithium chloride (1.3M solution in tetrahydrofuran, 0.78 mL , 1.01 mmol) was added drop wise over 10 minutes and the reaction mixture was stirred at this temperature for a further 15 minutes to afford a solution of pyrimidin-2-ylmagnesium chloride. This procedure was repeated to obtain in total 1 .94 mmol of pyrimidin-2-ylmagnesium chloride.

Step 2: Preparation of ethyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate salt with in situ oxidation

In a separate flask a mixture of ethyl 3-pyridazin-1-ium-1-ylpropanoate bromide (0.23 g, 0.88 mmol), copper(l) iodide (0.017 g, 0.09 mmol) and internal standard para-tolyl ether (0.09 g, 0.44 mmol) was purged with nitrogen, evacuated, and this process was repeated three times. Anhydrous tetrahydrofuran (2.2 mL ) was added and the resulting suspension was cooled to -10°C. To this mixture was added 1 .4 equivalents of the pre-formed pyrimidin-2-ylmagnesium chloride solution drop wise over 3 hours. An aliquot of the reaction mixture (0.1 m L) was removed and directly oxidatively quenched into a solution of iodine (30 mg, 0.24mmol) in dimethyl sulfoxide-d6 (0.5 mL ) to confirm an 80% yield of ethyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate (by reference to the ¹H NMR internal standard) as an undefined mixture of chloride, bromide or iodide salts.

¹H NMR (400 MHz, DMSO-d₆) 10.28 (d, 1 H), 10.25 (d, 1 H), 9.40 (d, 1 H), 9.19 (d, 2H), 7.82 (t, 1 H), 5.19 (t, 2H), 4.08 (q, 2H), 3.24 (t, 2H), 1.18 (t, 3H)

Example 6: Preparation of ethyl 3-(4-pyrimidin-2-yl-4H-pyridazin-1-yl)propanoate using a 2,2,2- trifluoroacetate salt of a compound of formula (IV)

Step 1 : 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, 1 H), 9.60-9.66 (m, 1 H), 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.

Step 2: Preparation of pyrimidin-2-ylmagnesium chloride. lithium chloride

A solution of 2-iodopyrimidine (0.26 g, 1 .27 mmol) in anhydrous tetrahydrofuran (2.5 mL ) was purged with nitrogen, evacuated, and this process was repeated three times. After cooling to -15°C a solution of isopropylmagnesium chloride lithium chloride (1 .3M solution in tetrahydrofuran, 1.11 mL , 1 .44 mmol) was added drop wise over 10 minutes and the reaction mixture was stirred at this temperature for a further 15 minutes to afford a solution of pyrimidin-2-ylmagnesium chloride. Step 3: Preparation of ethyl 3-(4-pyrimidin-2-yl-4H-pyridazin-1-yl)propanoate

In a separate flask a mixture of ethyl 3-pyridazin-1-ium-1-ylpropanoate 2,2,2-trifluoroacetate (0.25 g, 0.85 mmol), copper(l) iodide (0.032 g, 0.17 mmol) and internal standard para-tolyl ether (0.084 g, 0.42 mmol) was purged with nitrogen, evacuated, and this process was repeated three times. Anhydrous tetrahydrofuran (1 mL ) was added and the resulting suspension was again purged with nitrogen and cooled to -10°C. To this mixture was added the pre-formed pyrimidin-2-ylmagnesium chloride solution drop wise over 1 hour, followed by stirring for an additional 50 minutes. An aliquot was removed from the reaction mixture and quenched into a mixture of acetic acid-d₄ (0.15 mL ) and dimethyl sulfoxide-d6 (0.4 mL ) to confirm a 67% yield of ethyl 3-(4-pyrimidin-2-yl-4H-pyridazin-1-yl)propanoate (by reference to the ¹H NMR internal standard). ¹H NMR (400 MHz, CD₃CO₂D/DMSO-d₆) 8.68 (d, 2H), 7.27 (t, 1 H), 6.60 (t, 1 H), 6.29 (d, 1 H), 4.68 (ddd, 1 H), 4.16 (t, 1 H), 3.99 (q, 2H), 3.54 (m, 2H), 2.51 (t, 2H), 1.11 (t, 3H)

Example 7: Preparation of ethyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate salt using an alternative copper catalyst and in situ oxidation

Step 1 : Preparation of pyrimidin-2-ylmagnesium chloride. lithium chloride

A solution of 2-iodopyrimidine (0.1 g, 0.48mmol) and internal standard para-tolyl ether (0.044 g, 0.22 mmol) in anhydrous tetrahydrofuran (1.2 mL ) was purged with nitrogen, evacuated, and this process was repeated three times. After cooling to -15°C a solution of isopropylmagnesium chloride lithium chloride (1.3M solution in tetrahydrofuran, 0.39 mL , 0.506 mmol) was added drop wise over 10 minutes. The reaction mixture was stirred at this temperature for 15 minutes, then cooled to -70°C. This procedure was repeated (but without the ¹H NMR internal standard the second time) to obtain, in total, 1.94 mmol of pyrimidin-2-ylmagnesium chloride solution.

Step 2: Preparation of ethyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate salt using alternative copper catalyst and in situ oxidation In a separate flask a mixture of ethyl 3-pyridazin-1-ium-1-ylpropanoate bromide (0.115 g, 0.44 mmol) and copper(l) cyanide di(lithium chloride) complex (1 M solution in tetrahydrofuran, 0.044 mL , 0.044 mmol) in anhydrous tetrahydrofuran (0.5 mL ) was purged with nitrogen, evacuated, and this process was repeated three times. After cooling to -70°C half the pyrimidin-2-ylmagnesium chloride solution was added drop wise and the reaction mixture was stirred at this temperature for 15 minutes then warmed to -10°C. After stirring for 3 hours the remaining pyrimidin-2-ylmagnesium chloride solution was added drop wise and stirring was continued at -10°C for a further 45 minutes. An aliquot of the reaction mixture (0.1 mL ) was removed and directly oxidatively quenched into a solution of iodine (0.025 g, 0.2 mmol) in dimethyl sulfoxide-d6 (0.6 mL ) to confirm a 63% yield of ethyl 3-(4-pyrimidin-2- ylpyridazin-1-ium-1-yl)propanoate (by reference to the ¹H NMR internal standard) as an undefined mixture of chloride, bromide or iodide salts. ¹H NMR (400 MHz, DMSO-d₆) 10.30 (d, 1 H), 10.27 (d, 1 H), 9.40 (d, 1 H), 9.19 (d, 2H), 7.83 (t, 1 H), 5.19 (t, 2H), 4.08 (q, 2H), 3.24 (t, 2H), 1.18 (t, 3H)

Example 8: Alternative preparation of ethyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate salt

Step 1 : Preparation of pyrimidin-2-ylmagnesium chloride

A solution of 2-iodopyrimidine (0.51 g, 2.45 mmol) in anhydrous tetrahydrofuran (5 mL ) was purged with nitrogen, evacuated, and this process was repeated three times. After cooling to -12°C a solution of isopropylmagnesium chloride (2M solution in tetrahydrofuran, 1.64 mL , 3.28 mmol) was added drop wise over 10 minutes and the reaction mixture was stirred at this temperature for 5 minutes. Additional isopropylmagnesium chloride (2M solution in tetrahydrofuran, 0.40 mL , 0.80 mmol) was added drop wise over 10 minutes and after stirring for a further 5 minutes an aliquot was removed and quenched into methanol-d₄ (0.6 mL ) to confirm a 99% yield of 2-deuteriopyrimidine (by reference to the ¹H NMR internal standard) as evidence of pyrimidin-2-ylmagnesium chloride formation. ¹H NMR (400 MHz, CD₃OD) 8.80 (d, 2H), 7.55 (t, 1 H)

In a separate flask a mixture of ethyl 3-pyridazin-1-ium-1-ylpropanoate bromide (0.43 g, 1.64 mmol), copper(l) iodide (0.031 g, 0.164 mmol) and internal standard para-tolyl ether (0.162 g, 0.818 mmol) was purged with nitrogen, evacuated, and this process was repeated three times. Anhydrous tetrahydrofuran (2 mL ) was added and the resulting suspension was cooled to -10°C. To this mixture was added the pre-formed pyrimidin-2-ylmagnesium chloride solution drop wise whilst maintaining a reaction temperature of -10°C. The reaction mixture was allowed to slowly warm overnight then stirred for an additional 5 hours at room temperature. An aliquot of the reaction mixture (0.1 mL ) was removed and directly quenched into a mixture of acetic acid-d3 (0.16 mL ) and dimethyl sulfoxide-d6 (0.5 mL ) to confirm an 40% yield of ethyl 3-(4-pyrimidin-2-yl-4H-pyridazin-1-yl)propanoate (by reference to the ¹H NMR internal standard).

¹H NMR (400 MHz, CD₃CO₂D/DMSO-d₆) 8.68 (d, 2H), 7.27 (t, 1 H), 6.60 (t, 1 H), 6.29 (d, 1 H), 4.68 (ddd, 1 H), 4.16 (t, 1 H), 3.99 (q, 2H), 3.54 (m, 2H), 2.51 (t, 2H), 1.11 (t, 3H)

Example 9: Preparation of ethyl 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoate 2,2,2- trifluoroacetate

Step 1 : Preparation of pyridazin-3-ylmagnesium chloride. lithium chloride

A solution of 3-iodopyridazine (0.4 g, 1.94 mmol) in anhydrous tetrahydrofuran (4 mL ) was purged with nitrogen, evacuated, and this process was repeated three times. After cooling to -15°C a solution of isopropylmagnesium chloride lithium chloride (1 3M solution in tetrahydrofuran, 1 .72 mL , 2.33 mmol) was added dropwise over 5 minutes. The solution of pyridazin-3-ylmagnesium chloride was then cooled to -70°C.

Step 2: Preparation of ethyl 3-(4-pyridazin-3-ylpyridazin-1-ium-1-yl)propanoate 2,2,2-trifluoroacetate with in situ oxidation

In a separate flask a solution of ethyl 3-pyridazin-1-ium-1-ylpropanoate bromide (0.56 g, 2.14 mmol) and copper (I) iodide (0.037 g, 0.19 mmol) in anhydrous tetrahydrofuran (5 mL ) was purged with nitrogen, evacuated, and this process was repeated three times. After cooling to -70°C the solution of pyridazin-3-ylmagnesium chloride was added drop wise and the reaction mixture was then allowed to warm through a sequence of temperatures and times: stirred at -60°C for 30 minutes; warmed to - 20°C over 30 minutes then stirred for 20 minutes; warmed to -5°C over 30 minutes then stirred at -5°C for 20 minutes; warmed to 3°C over 30 minutes then stirred for 45 minutes; warmed to 12°C over 18 hours; finally warmed to room temperature and stirred for 24 hours. The reaction mixture was then cooled to -5°C and chloranil (0.48 g, 1 .94 mmol) was added in one portion. The reaction mixture was stirred at 0°C for 15 minutes then at room temperature for 1 hour. The reaction mixture was concentrated and the solid residue was washed with ethanol. The residue was purified by preparative reverse phase HPLC (trifluoroacetic acid was present in the eluent) to afford ethyl 3-(4-pyridazin-3- ylpyridazin-1-ium-1-yl)propanoate trifluoroacetate (0.051 g, 10% yield). ¹H NMR (400 MHz, CD₃OD) 10.34 (d, 1 H), 10.07 (d, 1 H), 9.45 (dd, 1 H), 9.33 (dd, 1 H), 8.67 (dd, 1 H), 8.03 (dd, 1 H), 5.20 (t, 2H), 4.15 (q, 2H), 3.31 (t, 2H), 1.24 (t, 3H)

Example 10: 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: 1 H NMR (400 MHz, methanol-d4) d 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 11: 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 CDCI3 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 1 hr then solid collected by filtration. The solid was triturate with THF( 50 ml) then filtered and then dried at 20 mbar at rt for 1 h. Solid is quite hygroscopic. Store under N2. Crude weight: 32g, quant NMR purity- 97%. Chem. Yield 95%

NMR data: 1H NMR (400 MHz, CDCI3) d 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 12: 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) d 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 13: Preparation of ethyl 3-pyridazin-1-ium-1-ylpropanoate tetrafluoroborate

Equipment: A clean and dry 50 mL , 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 mL 9 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: 1 H NMR (400 MHz, DMSO) d 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 14: Preparation of methyl 3-pyridazin-1-ium-1-ylpropanoate tetrafluoroborate

Equipment: clean and dry 100 mL , 3 neck Reaction Flask (RF) fitted with thermometer through pocket, N2 inlet.

Procedure: Pyridazine (5.00 g, 61 .18mmol, 98%, 4.533 mL ) 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. Oh. 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. Oh. 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). 1 HNMR 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 d= 9.47 and 9.46 and the peak of Pyridazine appear at d= 9.23 and 8.23

Workup: The reaction mixture was concentrated to dryness under reduced pressure and submitted for 1 HNMR: 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; tetrafluoro borate as a thick light yellowish liquid (15.7g).

Isolated Yield: 15.7g (Purity: 93.6%). Yield: 94.4%

NMR data: 1 H NMR (400 MHz, MeOD) d 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 15: Preparation of methyl 3-pyridazin-1-ium-1-ylpropanoate chloride

Equipment: A clean and dry 50 mL , 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.,

0.002 mL ) 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) d 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-CI ], (HSS T3 GENERAL 1-6 min method)

Example 16: 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: Pvridazine (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) d 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 17: 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 1 hr. It was then concentrated and stripped up with toluene.

Crude Yield: 4.51 g, (Q-Purity: 69.2%) Yield: 94%

NMR data: 1 H NMR (400 MHz, MeOD) d 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 18: 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: 1 H NMR (400 MHz, DMSO) d 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 19: 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 (10 mL) 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: 1 H NMR (400 MHz, D20) d 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, 1 H) 9.70 - 9.78 (m, 1 H)

LCMS data: 0.14 min, ms esi += 153 [M+H-Br-], (HSS T3 GENERAL 1-6 min method)

Example 20: 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 1 HNMR 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: 1 H NMR (400 MHz, MeOD) d ppm: 3.15 (m, 2H) 5.04 (m, 2 H) 8.46 (m, 1 H) 8.51 (m, 1 H) 9.45 (m, 1 H) 9.78 (m, 1 H)

Example 21: Preparation of 3-pyridazin-1-ium-1-ylpropanenitrile bromide

Equipment: 50 mL 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® (CH2CI2: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: 1 H NMR (400 MHz, DMSO-d6) d 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 22: Preparation of ethyl 3-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)propanoate chloride

Step 1 : Preparation of pyrimidin-2-ylmagnesium chloride

To a 5ml_ MW vial under argon, charged with 2-lodopyrimidine (1.5 equiv. 0.092 g, 0.441 mmol), THF (2 mL) was added Isopropyl magnesium chloride (2.0 mol/L) in diethyl ether (1.5 equiv. 0.22 mL, 0.441 mmol). The mixture was stirred for 30min at -10 - 0°C.

Step 2: Preparation of 2,2-dimethylpropyl 2-(4-pyrimidin-2-yl-4H-pyridazin-1-yl)ethanesulfonate

The Grignard suspension was added to a 10 mL EasyMax vial under argon, containing ethyl 3- pyridazin-1-ium-1-ylpropanoate;bromide (0.1 g, 0.294 mmol, 1.00), Copper(l) Iodide (10mol%, 5.6 mg) and THF (8 mL) within 5 min. (prepared 1 hour prior to addition to get a cloudy solution).

After 1 h LCMS indicate intermediate as main product and not properly isolated.

LCMS data: 2.17 min, ms esi+=339 [M+H], (Standard Long method)

Step 3: Preparation of 2,2-dimethylpropyl 2-(4-pyrimidin-2-ylpyridazin-1-ium-1-yl)ethanesulfonate chloride

A solution of Iodine (1 .0 equiv., 74 mg, 0.294 mmol) in THF (1 mL) was added to the brown suspension then stirred for 1 h at RT then the reaction mass was concentrated under vacuum to give 340mg of Crude product. qNMR indicate 50% conversion (0.1471 mmol of 2,2-dimethylpropyl 2-(4-pyrimidin-2-yl-4H-pyridazin-1- yl)ethanesulfonate)

NMR data: 1 H NMR (400 MHz, MeOD) d ppm 3.03 (s, 9 H) 4.03 (s, 2 H) 4.29 (t, J=6.42 Hz, 2 H) 5.45 (t, J=6.42 Hz, 2 H) 7.74 (t, J=4.77 Hz, 1 H) 9.14 (d, J=4.77 Hz,

2 H) 9.47 (dd, J=6.05, 2.38 Hz, 1 H) 10.18 (d, J=5.50 Hz, 1 H) 10.42 - 10.46 (m, 1 H)

LCMS data: 1.57 min, ms esi+=337 [M+H], (Standard Long method)

Example 23: Cobalt-Catalyzed Zinc-Insertion General Procedure

A dry and argon flushed flask equipped with a large magnetic stirring bar, was charged with CoCI2 (26 mg, 0.2 mmol, 10 mol%). The salt was dried under vacuum until the colour changed from purple to blue. Then, Zn(OPiv)2 (483 mg, 2.0 mmol, 1 .0 equiv) and zinc dust (429 mg, 6.6 mmol, 3.3 quiv) were added, followed by PhCN (4 mL). The zinc was activated with dibromoethane (0.02 mL) (no heating, simply stirring for about 1 min) and subsequently 2-chloropyrimidine (229 mg, 2.0 mmol, 1 .0 equiv) was added as a solution in PhCN (2 mL). The reaction was stirred at 25 °C for up to 48 h and monitored via GC Analysis (after quench with iodine). In this case 2-iodopyrimidine was obtained in a 75% GC-yield after stirring the reaction for 48 h before quench with iodine.

Example 24: Cobalt-Catalyzed Zinc-Insertion on 2-chloropyrimidine

The above general procedure was used to screen the following conditions shown in table 1 below. In this case the reaction was stirred for 15 h before quenching with iodine.

Table 1 : Screening of the cobalt-catalyzed zinc insertion into the carbon-chloride bond.

All reactions have been performed on a 1 .0 mmol scale under inert atmosphere. Yields are calculated yields to an internal standard.

The above general procedure was used to screen the following conditions shown in table 2 below.

Table 2: Solvent screening of the cobalt-catalyzed zinc insertion into the carbon-chloride bond.

The above general procedure was used to screen the following conditions shown in table 3 below.

Table 3: Screening of different zinc salts for the cobalt-catalyzed zinc insertion into the carbon-chloride bond.

Example 25: Cobalt-Catalyzed Zinc-Insertion on 2-bromopyrimidine

Using the above general procedure with 2-bromopyrimidine under inert atmosphere 2-iodopyrimidine was obtained in a 76% GC-yield.

Example 26: 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 1 H NMR of this fraction shows major as desired mass along with impurity coming from DDQ.

Sample of crude was dissolved in D20 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

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 Z_a, Zb, Z_c, Z_d, Z_e and Z_f below

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, R⁵⁹ 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;

(a) Reacting a compound of formula (II)

wherein A is as defined above and Y is selected from the group consisting of chloro, bromo, iodo and -OS(O)₂CF₃, with

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

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 any one of claims 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 a 6-membered heteroaryl selected from the group consisting of formula A-la, A-lla, A-llla and A-Vlla 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)₂0R¹⁰.

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

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

8. A process according to any one of claims 1 to 7, wherein the metal salt is selected from the group consisting of cobalt (II) chloride, cobalt (II) bromide, cobalt (II) nitrate, cobalt (II) sulfate, cobalt (II) acetate, magnesium chloride, magnesium bromide, zinc bromide, zinc chloride, zinc trifluoromethanesulfonate, zinc acetate, zinc pivalate and lithium chloride.

9. A process according to any one of claims 1 to 8, wherein the organometallic reagent in step (a) (i) is isopropylmagnesium chloride or isopropylmagnesium chloride. lithium chloride.

10. A process according to any one of claims 1 to 8, wherein step (a) (ii) is carried out in the presence of elemental Zn and Cobalt (II) chloride and Zinc chloride or Zinc Pivalate.

11. A process according to claim 10, wherein the Cobalt (II) chloride is present in catalytic amounts.

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 (la) or a zwitterion of formula (lb),

wherein Y¹ is CI 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.