EA040702B1 - METHOD FOR OBTAINING PYRIDAZINONE HERBICIDE COMPOUNDS - Google Patents

Description

The present invention relates to a process for the preparation of pyridazinone herbicidal compounds. Such compounds are known, for example, from WO 2012/136703 and WO 2017/178582. As explained in these documents, such compounds are usually obtained by formation of the corresponding pyridazinonic acid chloride and its coupling with cyclohexanedione in the presence of a base. This reaction first provides an enol ester which can be rearranged to a compound of formula (I) using a catalytic amount of a cyanide source, eg acetone cyanohydrin. However, the obtained yield values are not optimal for large scale production and the use of highly toxic cyanides on an industrial scale is undesirable. Therefore, alternative, more efficient synthetic routes are required.

The present invention provides an alternative carbonylation arylation process that (i) eliminates the need to prepare the acid chloride; and (ii) eliminates the cyanide-catalyzed rearrangement.

The synthesis of enol esters by reacting aryl halides with cyclohexanedione and carbon monoxide in the presence of a base and a palladium catalyst has been described (Negishi, E., Liou, S., Xu, C., Shimoyama, I., Makabe, H. J., Mol. Cat. A: Chem., 1999, 143, 279). However, the reaction does not proceed after the production of enol esters, which can be isolated in good yield. It has now surprisingly been found that if the aryl group is replaced by a particular pyridazinone group present in a compound of formula (II), the resulting starting enol ester actually rearranges under the reaction conditions to form a compound of formula (I) in high yields.

Thus, in accordance with the present invention, there is provided a process for preparing a compound of formula (I),

where R ¹ is selected from the group consisting of hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl,

C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl-, C ₁ -C ₃ -alkoxy-C ₂ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl-, aryl and 5- or 6-membered heteroaryl, where heteroaryl contains from one to three heteroatoms, each of which is independently selected from the group consisting of oxygen, nitrogen and sulfur, and where the aryl and heteroaryl components may be optionally substituted;

R ² is C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl;

A ¹ is selected from the group consisting of O, C(O) and (CR7R ⁸ ); and each of R ⁴ , R ⁶ , R ⁷ and R ⁸ is independently selected from the group consisting of hydrogen and C ₁ -C ₄ -alkyl;

each of R ³ and R ⁵ is independently selected from the group consisting of hydrogen and C ₁ -C ₄ alkyl, or together they may form a C ₁ -C ₃ alkylene chain;

wherein the method comprises carrying out the reaction of a compound of formula (II),

where X is a halogen, with a compound of formula (III),

where A ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are defined for formula (I) above, in a reaction medium containing (i) a palladium catalyst;

(ii) a suitable phosphine ligand or salt of a phosphine ligand;

(iii) a suitable basis; And

- 1 040702 (iv) carbon monoxide, to obtain a compound of formula (I).

C 1 -C ₆ -alkyl and C ₁ -C ₄ -alkyl groups mentioned above include, for example, methyl (Me,

CH ₃ ), ethyl (Et, C ₂ H ₅ ), n-propyl (n-Pr), isopropyl (i-Pr), n-butyl (n-Bu), isobutyl (i-Bu), sec-butyl and tert-butyl (t-Bu).

Halogen (or halo) includes fluorine, chlorine, bromine and iodine.

C ₁ -C ₆ haloalkyl includes, for example, fluoromethyl-, difluoromethyl-, trifluoromethyl-, chloromethyl-, dichloromethyl-, trichloromethyl-, 2,2,2-trifluoroethyl-, 2-fluoroethyl-, 2-chloroethyl-, pentafluoroethyl- , 1,1-difluoro2,2,2-trichloroethyl-, 2,2,3,3-tetrafluoroethyl-, 2,2,2-trichloroethyl-, heptafluoro-n-propyl and perfluoro-n-hexyl. C ₁ -C 4 haloalkyl includes, for example, fluoromethyl-, difluoromethyl-, trifluoromethyl-, chloromethyl-, dichloromethyl-, trichloromethyl-, 2,2,2-trifluoroethyl-, 2-fluoroethyl-, 2-chloroethyl-, pentafluoroethyl-, 1,1-difluoro2,2,2-trichloroethyl-, 2,2,3,3-tetrafluoroethyl-, 2,2,2-trichloroethyl- and heptafluoro-n-propyl-. Preferred C ₁ -C ₆ haloalkyl groups are fluoroalkyl groups, in particular difluoroalkyl and trifluoroalkyl groups, eg difluoromethyl and trifluoromethyl.

C ₃ -C ₆ -cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

C ₁ -C ₃ -alkoxy-C ₁ -C ₃ -alkyl- includes, for example, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, n-propoxymethyl, n-propoxyethyl, isopropoxymethyl or isopropoxyethyl.

C ₁ -C ₃ -alkoxy-C2-C ₃ -alkoxy-C ₁ -C ₃ -alkyl- includes, for example, methoxyethoxymethyl-.

The term nitro as used in this document refers to the -NO2 group.

The term aryl as used herein refers to an unsaturated aromatic carbocyclic group of 6-10 carbon atoms having one ring (e.g. phenyl) or multiple fused (fused) rings, at least one of which is aromatic (e.g., indanyl, naphthyl). Preferred aryl groups include phenyl, naphthyl, and the like. Most preferably, the aryl group is a phenyl group. The phenyl ring may be unsubstituted or in mono- or polysubstituted form, in which case the substituents may optionally be in the ortho, meta and/or para position(s).

A 5- or 6-membered heteroaryl group, wherein the heteroaryl contains one to three heteroatoms each independently selected from the group consisting of oxygen, nitrogen, and sulfur, includes, for example, furanyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl and triazolyl. The heteroaryl component may optionally be mono- or polysubstituted, as described.

If the aryl or heteroaryl components described above are substituted, one or more substituents are preferably selected from the group consisting of halogen, C ₁ -C 4 alkyl, C ₁ -C 4 haloalkyl, C ₁ -C ₃ alkoxy, cyano and nitro .

In one embodiment of the present invention, R ¹ is an optionally substituted heteroaryl.

In another embodiment of the present invention, R ¹ is an optionally substituted phenyl, preferably 3,4-dimethoxyphenyl.

In one embodiment of the present invention, R ² is methyl.

In a particularly preferred embodiment of the present invention, R ¹ is 3,4-dimethoxyphenyl and R ² is methyl.

In a preferred embodiment of the present invention, X is Br or Cl, most preferably Br.

In one embodiment of the present invention, A ¹ is CR7R ⁸ and R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen. Thus, in a particularly preferred embodiment of the present invention, the compound of formula (III) is cyclohexanedione.

In one embodiment of the present invention, A ¹ is CR ⁷ R ⁸ and R ⁴ , R ⁶ , R ⁷ and R ⁸ are hydrogen, and R ³ and R ⁵ together form an ethylene chain.

In a particularly preferred embodiment of the present invention A ¹ is CR ⁷ R ⁸ and R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen, R ¹ is 3,4-dimethoxyphenyl and R ² is methyl.

Suitable palladium catalysts (i) include, without limitation, Pd(OAc) ₂ , PdCl ₂ , Pd/C, PdBr ₂ , PdCl ₂ (PhCN) ₂ , Pd ₂ dba ₂ , Pd(PPh ₃ ) ₄ and PdCl 2 (cinnamyl) 2 . The most preferred catalyst is Pd(OAc) ₂ . The amount of palladium catalyst is 0.0001 to 0.05 equivalents, more preferably 0.0001 to 0.001 equivalents.

Suitable phosphine ligand or salts of phosphine ligands (ii) include, without limitation, monodentate phosphines such as Ph ₃ P, Cy ₃ P, nBuPAd ₂ , tBu ₃ P.HBF ₄ and XPhos, also bidentate ligands such as Xantphos, Josiphos, DPEPhos, dcpb, dcpp and BINAP. The most preferred phosphine ligands are Xantphos and DPEPhos if X=Br and dcpb if X=Cl. The amount of phosphine ligands is 0.0001 to 0.05 equivalents, more preferably 0.0001 to 0.001 equivalents.

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Suitable bases (iii) include, without limitation, inorganic bases such as

K2CO3, Cs ₂ CO3, Na2CO3, NaOH as well as amine bases such as triethylamine, diisopropylethylamine and DBU. The most preferred bases are triethylamine and diisopropylethylamine.

The process of the present invention is carried out in the presence of carbon monoxide, typically in a carbon monoxide atmosphere. The pressure is 1 to 50 bar, more preferably 2 to 10 bar. Alternatively, carbon monoxide can be generated during the process using a suitable carbon monoxide generator or a precursor thereof.

In a preferred embodiment of the present invention, the reaction medium further comprises a solvent (v). Suitable solvents include, without limitation, polar aprotic solvents such as acetonitrile, anisole, dioxane, THF, EtOAc, MTBE, PrCN. The most preferred solvent is acetonitrile.

Additionally provided is a compound of formula (IIa),

^R2

(On) Oh

K ^1E 2 where R ^1a is an optionally substituted phenyl and R ² and X are as defined above. Additionally provided is a compound of formula (IIa1),

where R ² and X are defined above;

R3 is selected from the group consisting of halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₃ alkoxy, cyano and nitro; and n=0, 1, 2, or 3.

The present invention also further provides a compound of formula (IIa) wherein R ² is methyl;

X is Br; And

R ^1a is 3,4-dimethoxyphenyl (i.e. 4-bromo-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3one/compound of formula (IIa1a))

The following scheme describes the reactions of the present invention in more detail. The definitions of substituents are the same as defined above.

Scheme 1

- 3 040702

Typically, small amounts of the enol ester of formula (VIII) are continuously formed in the presence of a large effective amount of excess cyclohexanedione and base.

Step (a).

Compounds of formula (II) can be obtained by carrying out the reaction of pyridazinone of formula (IX)

where R ² is defined above for a compound of formula (I), with boronic acid of formula (IV)

BUT^^OH

R (IV), where R ¹ is defined above for the compound of formula (I), in the presence of a base, a copper catalyst and oxygen, as, for example, described in Monnier, F., Tailefer, M., Topics in Organomet. Chem., 2013, 46, 173.

Suitable copper catalysts include, without limitation, CuCl, CuBr, CuI, Cu(OAc) ₂ and Cu ₂ O. The most preferred catalyst is Cu(OAc) ₂ .

Suitable bases include, without limitation, alkali metal hydroxides and carbonates such as NaOH, KOH, K ₂ CO ₃ and Na ₂ CO ₃ , as well as amine bases such as Et ₃ N, iPr ₂ NEt and pyridine. The most preferred bases are pyridine and Na ₂ CO ₃ .

The reactions between compounds of formula (IX) and (IV) are preferably carried out in the presence of a solvent. Suitable solvents include, without limitation, polar organic solvents such as DMF, 1,2-dichloroethane, acetonitrile, EtOAc, iPrOAc, dimethylacetamide, sulfolane, and NMP. The most preferred solvents are DMF, dimethylacetamide and NMP.

The reaction can be carried out at a temperature of 25 to 120°C, more preferably 40 to 80°C.

Preferably, the reaction proceeds under continuous purging with an oxygen/nitrogen mixture. The oxygen concentration may be from 5 to 100%, preferably from 5 to 25%, more preferably 22% (air).

Step (b).

Alternatively, compounds of formula (II) can be prepared by carrying out the reaction of pyridazinone of formula (IX)

where R ² is defined above for the compounds of formula (I); and X is chlorine, bromine or iodine, with a compound of formula (VII)

^R1- ! (VII), where R ¹ is selected from the group consisting of C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, C ₁ -C ₃ -alkoxy, C ₁ -C ₃ -alkyl-, C ₁ -C ₃ -alkoxy, C ₂ -C ₃ -alkoxy, C ₁ -C ₃ -alkyl-, C ₁ -C ₆ -haloalkyl, C ₂ -C ₆ -haloalkenyl, C ₁ -C ₃ -alkoxy-C 1 -C ₃ -haloalkyl, in the presence of a base.

Step (c).

Alternatively, compounds of formula (II) where X is chlorine, R ¹ is aryl and 5- or 6-membered heteroaryl, where heteroaryl contains one to three heteroatoms, each independently selected from the group consisting of oxygen, nitrogen and sulfur, and where the aryl and heteroaryl components may be optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, acetylamino, nitro , and R ² is C1-C ₆ -alkyl or C ₃ -C ₆ -cycloalkyl, can be obtained by carrying out the reaction of the aldehyde of formula (VI)

where R ¹ is aryl and 5- or 6-membered heteroaryl, where heteroaryl contains from one

- 4 040702 up to three heteroatoms, each independently selected from the group consisting of oxygen, nitrogen and sulfur, and where the aryl and heteroaryl components may be optionally substituted with one or more substituents selected from the group consisting of halogen, C ₁ -C ₃ -alkyl,

C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkoxy, cyano, acetylamino, nitro, with phosphonate of formula (V)

Β ⁹ Ο _χ θ θ ^X (V), where X is chlorine; And

R ⁹ is C ₁ -C ₃ -alkyl, in the presence of a base and an alcoholic solvent.

Suitable bases include, without limitation, alkali metal alkoxides such as NaOEt, NaOMe, KOtBu, and NaOtBu.

Suitable alcoholic solvents include, without limitation, MeOH, EtOH, iPrOH, and tBuOH.

The reaction can be carried out at -25 to 40°C, preferably 0 to 20°C.

Alternatively, compounds of formula (II) wherein R ¹ is 3,4-dimethoxyphenyl, R ² is defined in formula (I) and X is Br can be prepared by a process which comprises reacting a compound of formula (IX)

with a halogenating agent to give a compound of formula (X)

where X is Br and R ⁹ is selected from the group consisting of Cl, Br and I, preferably is Cl;

and then reacting a compound of formula (X) with a compound of formula (XI)

in the presence of a radical initiator and a base, or by irradiating the reaction mixture with visible light in the presence of a suitable sensitizer and a base.

Suitable halogenating (chlorinating agents) include sodium hypochlorite, t-butyl hypochlorite and other alkyl hypochlorites, chlorine, NCS, trichloroisocyanuric acid. Sodium hypochlorite is preferred.

The initial reaction can be carried out under homogeneous conditions (with tert-butyl hypochlorite) or in a two-phase system (with aqueous sodium hypochlorite) and an organic solvent in the presence of a neutralizing agent (acid, buffer) which is added simultaneously with the sodium hypochlorite solution.

Alternatively, the reaction can simply be carried out in water (with sodium hypochlorite or chlorine), with the product isolated by filtration.

Suitable solvents include chlorobenzene, dichloromethane, toluene and MTBE. Chlorobenzene and dichloromethane are preferred.

Suitable acidifiers include mineral acids (eg HCl, H2SO4), carboxylic acids (eg AcOH), phosphate buffer, sodium bicarbonate.

The initial reaction can be carried out at -5 to 80°C, preferably 25 to 40°C.

Compound (X) can be isolated in pure form by crystallization from the organic solvent used for the reaction, or by simple evaporation of the organic layer. It can also be used in solution in a subsequent reaction.

In case of converting compound (X) to compound (II), suitable solvents include toluene, chlorobenzene, 1,2-dichlorobenzene, benzonitrile, TBME, acetonitrile, butyronitrile, dichloromethane, 1,2-dichloroethane, ethyl acetate, isopropyl acetate. Chlorobenzene is preferred.

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Phase transfer catalysts can also be used to improve the rate and yield of the reaction and include, for example, Bu ₄ NCl and Aliquat 336.

Radical initiators include, without limitation, AIBN, benzoyl peroxide, lauroyl peroxide, bis(tert-butylcyclohexyl)peroxydicarbonate (DCHPC), tert-butyl hydroperoxide, cumene hydroperoxide (CHP), methyl ethyl ketone peroxide (MEKP), potassium peroxodisulfate. Cumene hydroperoxide (CHP) and methyl ethyl ketone peroxide (MEKP) are preferred.

It should also be noted that a compound of formula (IX) can be converted to a compound of formula (II) in a one-step procedure. Thus, the compound (X) can be formed (and continuously consumed after formation) in situ, which allows the conversion of (IX) to (II) in one step. In addition, a stoichiometric amount of base is not required in this case. Typically, a sodium hypochlorite solution is added to a mixture of compound (IX), 1,2-dimethoxybenzene, an organic solvent, an aqueous buffer solution, a phase transfer catalyst, and a radical initiator. The radical initiator can also be added at the same time as the sodium hypochlorite solution.

Alternatively, a photochemically catalyzed procedure can be used. Suitable bases in this aspect include, without limitation, inorganic bases such as K ₂ CO ₃ , Cs ₂ CO ₃ , Na ₂ CO ₃ , NaHCO ₃ , sodium acetate, potassium acetate, NaOH, and phosphate buffer.

The reaction can be carried out at a temperature of 20 to 80°C, preferably 30 to 40°C.

Alternatively, a compound of formula (II) wherein X=6 rom and R ¹ =aryl (particularly 3,4-dimethoxyphenyl) as defined above can be obtained after electrolysis of pyridazinone (IX) in the presence of a compound of formula (XI) and electrolyte in an organic solvent. This procedure has the advantage that it is not necessary that the reaction proceed through an intermediate compound of formula (X).

The electrolysis can be carried out in a batch type reaction mode, in which a certain current is passed through the reaction mixture using electrodes connected to a power source, or in a flow type reaction mode, consisting in passing the reaction mixture through a flow cell. The most preferred electrolysis reaction mode is flow electrolysis.

Suitable electrode materials include, without limitation, graphite, glassy carbon, DSA, Ir/Ta MOX, Ir/Ti MOX as the anode material, and graphite, glassy carbon, steel, copper, platinum as the cathode material. The preferred material is Ir/Ta MOX for the anode and steel (V2A) for the cathode.

Suitable electrolytes include, without limitation, salts of the type A+B ^- where A ⁺ =Na ⁺ , K ⁺ , NR ₄ ⁺ (while R=H or alkyl) and where B'=acetate, pivalate, benzoate, fluoride. Additional electrolytes include, without limitation, organic electrolytes, namely tetramethylguanidine, DBU, triethylamine, 4-N,N'dimethylaminopyridine, HFIP, acetic acid. Preferred electrolytes are carboxylate salts in the form of sodium and potassium pivalate.

Suitable solvents include, but are not limited to, the alcohols MeOH, EtOH, iPrOH, tBuOH, HFIP, with MeOH being the preferred solvent.

The electrolysis can be carried out at -20 to 60°C, preferably 5 to 35°C.

Thus, the present invention also further provides a compound of formula (X)

where R ⁹ is selected from the group consisting of Cl, Br and I, preferably represents Cl (ie 4-bromo2-chloro-6-methylpyridazin-3-one).

Step (d).

A compound of formula (I) can advantageously be prepared by reacting a compound of formula (II) with a compound of formula (III) in the presence of a base, a palladium catalyst, a suitable phosphine or phosphine salt, and carbon monoxide.

Suitable bases include, but are not limited to, inorganic bases such as K2CO3, Cs2CO3, Na2CO3, NaOH, as well as amine bases such as triethylamine, diisopropylethylamine, and DBU. The most preferred bases are triethylamine and diisopropylethylamine.

Suitable palladium catalysts include, without limitation, Pd(OAc) ₂ , PdCl ₂ , Pd/C, PdBr ₂ , PdCl ₂ (PhCN) ₂ , Pd ₂ dba ₂ , Pd(PPh ₃ ) ₄ and PdCl ₂ (cinnamyl) ₂ . The most preferred catalyst is Pd(OAc) ₂ . The amount of palladium catalyst is 0.0001 to 0.05 equivalents, more preferably 0.0005 to 0.005 equivalents.

Suitable phosphines and phosphine salts include, without limitation, monodentate phosphines such as Ph ₃ P, Cy ₃ P, nBuPAd ₂ , tBu ₃ P.HBF ₄ and XPhos, also bidentate ligands such as Xantphos,

- 6 040702

Josiphos, Dpephos, dcpb, dcpp and BINAP. The most preferred phosphine ligands are Xantphos and Dpephos if X=Br and dcpb if X=Cl. The amount of phosphine ligands is 0.0001 to 0.05 equivalents, more preferably 0.0005 to 0.005 equivalents.

The reaction is carried out in an atmosphere of carbon monoxide. The pressure is 1 to 50 bar, more preferably 2 to 10 bar.

The reactions between a compound of formula (II) and a compound of formula (III) are preferably carried out in the presence of a solvent. Suitable solvents include, without limitation, polar aprotic solvents such as acetonitrile, anisole, dioxane, THF, EtOAc, MTBE, PrCN. The most preferred solvent is acetonitrile.

The reaction can be carried out at a temperature of 20 to 120°C, preferably 40 to 70°C.

Various aspects and embodiments of the present invention will now be illustrated in more detail using the following non-limiting examples.

The following abbreviations are used:

s - singlet;

br s - wide singlet;

d - doublet;

dd - double doublet;

dt - double triplet;

t - triplet, tt - triplet, q - quartet, quin - quintuplet, sept - septet;

m - multiplet;

RT - retention time,

MH+ is the molecular weight of the molecular cation.

1H NMR spectra were recorded at 400 MHz, unless otherwise indicated, and chemical shifts were recorded in ppm.

Example 1 Preparation of 4-bromo-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3-one.

Example 1a. 4-Bromo-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3-one.

Cu(OAc) ₂ (1.15 g , 6.32 mmol) and pyridine (4.1 ml, 50 mmol). The resulting suspension was heated to 50° C. and a solution of 3,4-dimethoxyphenylboronic acid (7.05 g, 37.9 mmol) in anhydrous DMF (30 mL) was added over 4.5 h using a syringe pump. During the reaction, air was bubbled through the reaction mixture with vigorous stirring. The reaction mixture was stirred for an additional 2 hours and then cooled to ambient temperature. Dichloromethane (100 ml) was added followed by 1 M HCl (200 ml). The resulting mixture was stirred for 30 min, the organic layer was separated and the aqueous layer was extracted with dichloromethane (2x100 ml). The combined organic phase was washed with ice water (4x100 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give crude 4-bromo-2(3,4-dimethoxyphenyl)-6-methylpyridazin-3-one (10.21 d) as a brown solid. Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 71% (yield 88%). The crude product was suspended in TBME (50 ml) and stirred for 20 minutes, the TBME was decanted and the same procedure was repeated two more times. Drying the residue under high vacuum gave 4-bromo-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3one (6.30 g, 95% purity, 73% practical yield) as a light brown solid.

1H NMR (400 MHz, CDCl ₃ ): δ 7.58 (s, 3H), 7.16-7.12 (m, 2H), 6.95-6.92 (m, 1H), 3.92 ( s, 3H), 3.90 (s, 3H), 2.39 (s, 3H).

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Example 1b. An alternative way to obtain 4-bromo-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3one.

Step 1. 4-Bromo-2-chloro-6-methylpyridazin-3-one.

\^.Br ^N 'n^o

I

Cl

5-Bromo-3-methyl-1H-pyridazin-6-one (20.0 g, 103.8 mmol, 98.1% purity), dichloromethane (60 ml) and tert-butaiol (1 ml, 10.5 mmol ) were loaded into the reactor. Sodium hypochlorite solution (80.3 g, 116.4 mmol, 10.8%) and glacial acetic acid (6.67 g, 116.4 mmol) were added simultaneously at 23-27°C over 40 minutes. The mixture was diluted with dichloromethane (150 ml) and the phases were separated. The aqueous phase was extracted with dichloromethane (60 ml). The combined organic phase was dried over anhydrous Na ₂ SO ₄ and the solvent was completely removed by evaporation in a rotary evaporator under reduced pressure to obtain a white crystalline material (23.17 g, 99% purity by quantitative NMR analysis, mp 145-148° C diff.).

Ή NMR (400 MHz, CDC1 ₃ ): δ 7.54 (s, 1H), 2.35 (s, 3H).

Step 2 4-Bromo-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3-one.

4-Bromo-2-chloro-6-methylpyridazin-3-one (2.00 g, 8.9 mmol, 99% purity), 1,2-dimethoxybenzene (1.48 g, 10.7 mmol), bis( 4-tert-Butylcyclohexyl)peroxydicarbonate (0.19g, 0.48mmol), sodium bicarbonate (1.13g, 13.4mmol), tetrabutylammonium chloride (52mg, 0.18mmol), chlorobenzene (20g) and water (9 g) was loaded into the flask. The mixture was heated to 60° C. for 2 hours. The organic phase was separated and the aqueous phase was extracted with chlorobenzene (2x20 ml). The combined organic extract was dried over Na ₂ SO 4 and evaporated to give a brown oil (2.9 g). This material was analyzed by quantitative HPLC.

Example 1c. Alternative (single-step) route for obtaining 4-bromo-2-(3,4-dimethoxyphenyl)-6methylpyridazin-3-one.

5-Bromo-3-methyl-1H-pyridazin-6-one (3.0 g, 15.0 mmol, 94.5% purity), 1,2-dimethoxybenzene (41.4 g, 300 mmol), Aliquat® 336 (0.61 g, 1.5 mmol), chlorobenzene (47 ml) and phosphate buffer solution (38 ml, 38 mmol, 1 M, pH 7.2) were loaded into a double jacketed reactor. Sodium hypochlorite solution (10.6 g, 15.0 mmol, 10.6%) was added in one portion and the mixture was stirred for 10 minutes at room temperature (RT). A solution of methyl ethyl ketone peroxide (0.99 g, 1.5 mmol, 32% in a mixture of phthalate-free plasticizers) in chlorobenzene (9 ml) was added simultaneously with a solution of sodium hypochlorite (58.1 g, 82.0 mmol, 10.6 %) for about 3 hours while maintaining the temperature at 35°C (addition of sodium hypochlorite solution was completed 15 minutes earlier). During this time period, 4 consecutive portions of 5-bromo-3-methyl-1H-pyridazin-6-one were added (each portion 3.0 g, 15.0 mmol, 94.5% purity; total 12.0 g, 65.0 mmol) at intervals of 40 minutes between each portion. The reaction mixture was stirred for 1 h at 35°C. Residual active chlorine was removed with a solution of sodium metabisulphite (5 ml, 10%). The mixture was heated to 80°C and the aqueous lower layer was separated. The solvent and residual 1,2-dimethoxybenzene were removed by vacuum distillation. The hot melt of the product was diluted with 1-butanol (73.3 g) and the resulting solution was slowly cooled to 0°C. The resulting suspension was filtered and the product was dried in an oven at 60° C. under vacuum.

Ή NMR (400 MHz, CDCI3): δ 7.58 (s, 1H), 7.14-7.11 (m, 2H), 6.94-6.91 (m, 1H), 3.91 (s , 3H), 3.89 (s, 3H), 2.38 (s, 3H).

Example Id. An alternative way to obtain 4-bromo-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3one.

-8040702

A suspension of 5-bromo-3-methyl-1H-pyridazin-6-one sodium salt (0.177 g, 0.78 mmol) prepared in advance by deprotonation with NaH in THF and evaporation of the reaction mixture, and Pb(OAc) ₄ (0.437 g, 0.936 mmol) in veratrol (2.20 g, 15.6 mmol) was heated for 19 h at 100°C. The resulting brown reaction mixture was quenched by adding aq. saturated solution of NH ₄ Cl. The mixture was then extracted with DCM, the organic layer was washed with water and dried over anhydrous MgSO ₄ . Evaporation under reduced pressure provided the crude product as a solution in veratrol (2.45 g).

Example 1e. An alternative way to obtain 4-bromo-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3one.

Pb (OAc) ₄ (3.75 g, 6.77 mmol). The resulting black suspension was stirred at 80° C. for 16 hours. The reaction mixture was then cooled to ambient temperature and evaporated almost to dryness under reduced pressure. The residue was diluted with DCM and poured into aq. saturated solution of NaHCO ₃ . The resulting mixture was extracted with DCM (3x), the combined organic layer was washed with brine and dried over anhydrous MgSO ₄ . Evaporation under reduced pressure provided a crude product (2.50 g).

Example 1f. An alternative way to obtain 4-bromo-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3one.

To a solution of 5-bromo-3-methyl-1H-pyridazin-6-one (1.10 g, 5.35 mmol) and PhI(OAc) ₂ (2.13 g, 6.45 mmol) in trifluoroethanol (14 ml ) was added veratrol (1.52 g, 10.8 mmol) and the resulting mixture was stirred at 70°C for 24 hours the Reaction mixture was cooled to ambient temperature and evaporated under reduced pressure.

Example 1g. An alternative way to obtain 4-bromo-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3one.

Triethylamine (0.11 ml , 0.75 mmol) followed by the addition of (3,4-dimethoxyphenyl)-(2,4,6-trimethylphenyl)iodonium tetrafluoroborate (0.302 g, 0.528 mmol). The resulting suspension was stirred for 14 hours at ambient temperature (complete conversion of starting material). The reaction mixture was diluted with DCM, washed with aq. saturated NH4Cl solution, water and saline solution. The organic layer was dried over anhydrous MgSO4 and evaporated under reduced pressure to give a crude product (0.279 g).

- 9 040702

Example 1h. An alternative way to obtain 4-bromo-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3one is a photochemical method.

Option 1. Method without solids.

4-Bromo-2-chloro-6-methylpyridazin-3-one (5.0 g, 15.0 mmol, 94.5% purity), 1,2-dimethoxybenzene (5.7 g, 42 mmol), water ( 5.3 g, 30 mmol) ruthenium (bipyridine) dichloride hydrate (26 mg, 0.03 mmol), acetonitrile (21 g, 511 mmol) and potassium acetate (5.8, 60 mmol) were charged to the reactor. The mixture was irradiated in the wavelength range 420-460 nm (light source - Blue Tuna lamp from Kessil) for 2 hours at RT with stirring. The aqueous phases were removed by extraction. The solvent and residual 1,2-dimethoxybenzene were removed by vacuum distillation.

1H NMR (400 MHz, CDC^): δ 7.58 (s, 1H), 7.14-7.11 (m, 2H), 6.94-6.91 (m, 1H), 3.91 ( s, 3H), 3.89 (s, 3H), 2.38 (s, 3H).

Option 2. Suspension method.

4-Bromo-2-chloro-6-methylpyridazin-3-one (5.0 g, 15.0 mmol, 94.5% purity), 1,2-dimethoxybenzene (5.7 g, 42 mmol), ruthenium( bipyridine) dichloride hydrate (26 mg, 0.03 mmol), acetonitrile (21 g, 511 mmol) and potassium acetate (5.8, 60 mmol) were charged to the reactor. The mixture was irradiated in the wavelength range 420-460 nm (light source - Blue Tuna lamp from Kessil) for 2 hours at RT with stirring. The aqueous phases were removed by extraction. The solvent and residual 1,2-dimethoxybenzene were removed by vacuum distillation.

1H NMR (400 MHz, CDCl3): δ 7.58 (s, 1H), 7.14-7.11 (m, 2H), 6.94-6.91 (m, 1H), 3.91 (s , 3H), 3.89 (s, 3H), 2.38 (s, 3H).

Example 1i. An alternative way to obtain 4-bromo-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3one is an electrochemical method.

A solution of 5-bromo-3-methyl-1H-pyridazin-6-one (2.89 g, 15.0 mmol, 98% purity), veratrol (50.2 g, 360 mmol, 99% purity), potassium pivalate ( 2.21 g, 15.0 mmol, 95% purity in methanol (104 g, 3.26 mol, >99% purity) was pumped (500 ml/min) through a flow cell (undistributed, electrode surface: 80 cm, Ir /Ta MOX - anode, stainless steel - cathode, electrode-electrode distance = 1 mm) at a current density of 12.5 mA/cm ² . The mixture was circulated through the installation, which consisted of a storage tank, a pump, and an electrolyzer, until complete conversion of the starting material was obtained after 3 hours.

The same general procedure as described in Example 1a above was used to synthesize the compounds listed below.

- 10 040702

Example 2 4-Bromo-2-(4-methoxyphenyl)-6-methylpyridazin-3-one.

The crude 4-bromo-2-(4-methoxyphenyl)-6-methylpyridazin-3-one (2.17 g) was obtained as a pale brown solid. Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 61% (chemical yield 88%). The crude material was purified by silica gel chromatography (0-70% EtOAc in cyclohexane) to give 4-bromo-2-(4-methoxyphenyl)-6-methylpyridazin-3-one (1.10 g, 75%, 98% purity ) as a white crystalline solid.

¹ H NMR (400 MHz, CDCla): δ 7.57 (s, 1H), 7.54-7.47 (m, 2H), 7.09 (s, 1H), 7.00-6.94 ( m, 2H), 3.85 (s, 3H), 2.39 (s, 3H).

Example 3 4-Bromo-6-methyl-2-[4-(trifluoromethyl)phenyl]pyridazin-3-one.

The crude 4-bromo-6-methyl-2-[4-(trifluoromethyl)phenyl]pyridazin-3-one (2.17 g) was obtained as a pale beige solid. Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 59% (chemical yield 79%). The crude material was purified by silica gel chromatography (15-55% EtOAc in cyclohexane) to give 4-bromo-6-methyl-2-[4-(trifluoromethyl)phenyl]pyridazin-3-one (1.25 g, 77% , purity >99%) as a white crystalline solid.

1H NMR (400 MHz, CDCla): δ 7.80 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.8 Hz, 2H), 7.61 (s, 1H) , 2.41 (d, J=1.5Hz, 3H).

Example 4 4-(5-Bromo-3-methyl-6-oxopyridazin-1-yl)benzonitrile

The crude 4-(5-bromo-3-methyl-6-oxopyridazin-1-yl)benzonitrile (4.56 g) was obtained as a white solid. Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 33% (chemical yield 67%). The crude material was purified by silica gel chromatography (20-100% EtOAc in cyclohexane) to give 4-(5-bromo-3-methyl-6-oxopyridazin-1-yl)benzonitrile (1.56 g, 60%, 86 purity %) as a white crystalline solid.

1H NMR (400 MHz, CDCl ₃ ): δ 7.88-7.74 (m, 4H), 7.61 (s, 1H), 2.42 (s, 3H).

Example 5 4-Bromo-6-methyl-2-(p-tolyl)pyridazin-3-one

The crude 4-bromo-6-methyl-2-(p-tolyl)pyridazin-3-one (1.56 g) was obtained as a yellow solid. Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 78% (chemical yield 84%). The crude material was purified by silica gel chromatography (0-50% EtOAc in cyclohexane) to give 4-bromo-6-11 040702 methyl-2-(p-tolyl)pyridazin-3-one (1.1 g, 74%, 97% pure as a white crystalline solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.58 (s, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.31-7.22 (m, 2H), 2.40 (s, 3H), 2.39 (s, 3H).

Example 6 4-Bromo-6-methyl-2-(m-tolyl)pyridazin-3-one

The crude 4-bromo-6-methyl-2-(m-tolyl)pyridazin-3-one (1.96 g) was obtained as a yellow solid.

Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 67% (chemical yield 90%). The crude material was purified by silica gel chromatography (20-50% EtOAc in cyclohexane) to give 4-bromo-6-methyl-2-(mtolyl)pyridazin-3-one (1.22 g, 81%, 97% pure). as a white crystalline solid.

1H NMR (400 MHz, CDCl3): δ 7.59 (s, 1H), 7.41-7.32 (m, 3H), 7.25-7.18 (m, 1H), 2.41 (s , 3H), 2.39 (s, 3H).

Example 7 4-Bromo-6-methyl-2-(o-tolyl)pyridazin-3-one

The crude 4-bromo-6-methyl-2-(o-tolyl)pyridazin-3-one (3.94 g) was obtained as a yellow oil.

Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 33% (chemical yield 59%). The crude material was purified by silica gel chromatography (5-60% EtOAc in cyclohexane) to give 4-bromo-6-methyl-2-(otolyl)pyridazin-3-one (1.34 g, 56%, 91% purity). as a yellow crystalline solid.

1H NMR (400 MHz, CDCl3): δ 7.63 (s, 1H), 7.38-7.29 (m, 3H), 7.26-7.23 (m, 1H), 2.39 (s , 3H), 2.17 (s, 3H).

Example 8 N-[4-(5-Bromo-3-methyl-6-oxopyridazin-1-yl)phenyl]acetamide

The crude N-[4-(5-bromo-3-methyl-6-oxopyridazin-1-yl)phenyl]acetamide (1.52 g) was obtained as a yellow solid. Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 67% (chemical yield 61%). The crude material was purified by silica gel chromatography (50-100% EtOAc in cyclohexane) to give N-[4-(5-bromo-3-methyl-6-oxopyridazin-1-yl)phenyl]acetamide (0.725 g, 40% , 91% pure) as a yellow crystalline solid.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.60 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 2.40 (s, 3H), 2.19 (s, 3H).

Example 9 4-Bromo-2,6-dimethylpyridazin-3-one

Sodium hydride in paraffin oil (60%, 0.255 g, 6.66 mmol) was added to a solution of 5-bromo-3methyl-1H-pyridazin-6-one (1.03 g, 5.12 mmol) in DMF (7.2 ml) at 0°C. After stirring for 20 minutes, iodomethane (6.66 mmol, 0.417 mL) was added via syringe at rt. The reaction medium warmed up noticeably and turned dark purple. After stirring for 1 hour, the reaction

- 12 040702 the mixture was quenched by pouring into a mixture of an aqueous solution of NaHCO ₃ and Na ₂ S ₂ O ₃ . The mixture was extracted with EtOAc (2x) and the combined organic layer washed with water and brine. Drying over anhydrous Na ₂ SO ₄ and evaporation under reduced pressure provided 1.228 g of crude material as a black solid. Purification by silica gel chromatography (0-70% EtOAc in cyclohexane) provided 4-bromo-2,6dimethylpyridazin-3-one (0.736 g, 70.4%, >99.5% purity) as a white solid.

1H NMR (400 MHz, CDCl ₃ ): δ 7.51 (s, 1H), 3.8 (s, 3H), 2.32 (s, 3H).

Example 10 4-Bromo-2-butyl-6-methylpyridazin-3-one

^BrN'N ^O

4-Bromo-2-butyl-6-methylpyridazin-3-one was obtained using a procedure similar to that described in example 9, from 1-iodobutane as a light yellow oil (1.387 g, 93.7%, 99% purity).

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.48 (s, 1H), 4.19-4.12 (m, 2H), 2.32 (s, 3H), 1.84-1.73 (m, 2H), 1.44-1.33 (m, 2H), 0.96 (t, J=7.3, 3H).

Example 11 (2Z)-2-[(3,4-dimethoxyphenyl)hydrazono]propanal

ABOUT

II

L1

O ₄

A 5 L double jacketed reactor was charged with water (1.2 L) and cooled to 5°C. Slowly added concentrated sulfuric acid (104 ml, 1.90 mol) while maintaining the temperature below 25°C. When the internal temperature reached 5° C. again, 3,4-dimethoxyaniline (198.0 g, 1.27 mol) was added portionwise. A solution of sodium nitrite (88.3 g, 1.27 mol) in water (0.25 L) was added to the dark purple suspension over 40 min while maintaining the internal temperature below 5°C. The reaction mixture was stirred at 0°C for 90 min followed by the addition of a solution of 3-dimethylamino-2-methyl-2-propanal (137.2 g, 1.15 mol) and NaOAc (105.0 g, 1.27 mol) in water (0.75 l) for 1 hour while maintaining the internal temperature below 5°C. After the addition was complete, the reaction mixture was allowed to gradually reach 20° C. over 2.5 hours. The resulting black suspension was transferred to a 5 L Erlenmeyer flask and the reactor was washed with water (2 L) to remove most of the remaining precipitate. The solid product was filtered off, washed on the filter with water (1.5 L) and dried to constant weight at 50° C. and high vacuum for 40 h to give (2Z)-2-[(3,4-dimethoxyphenyl)hydrazono ]propanal (199 g, 92% purity, 71% yield) as a red solid. This material was pure enough to be used in the next step. After settling for 16 hours at RT, another portion of the product precipitated from the aqueous phase and this was also filtered off, washed and dried in vacuo to obtain a second batch of (2Z)-2-[(3,4-dimethoxyphenyl)hydrazono]propanal (43.7 g, 70% purity, 12% yield; 83% yield for both batches combined).

¹ H NMR (400 MHz, CDCl ₃ ): δ 9.49 (s, 1H), 8.10 (br s, 1H), 7.00 (d, J=2.6 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.70 (dd, J=8.6, 2.4 Hz, 1H), 3.94 (s, 3H), 3.88 (s, 3H) , 1.98 (s, 3H).

Example 12 4-Chloro-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3-one

(2Z)-2-[(3,4-dimethoxyphenyl)hydrazono]propanal (4.80 g, 96% purity, 20.7 mmol) was suspended in EtOH (62 mL). Triethyl 2-chloro-2-phosphonoacetate (6.57 g, 24.9 mmol) was added at 0° C. followed by NaOEt (2.20 g, 31.1 mmol). The reaction mixture was stirred at 0°C for 45 min before adding another portion of NaOEt (2.20 g, 31.1 mmol). After stirring for an additional 45 minutes, the reaction mixture was quenched by adding aq. saturated solution

- 13 040702

_NaHC03 . The resulting mixture was extracted with DCM (3x), the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting residue was suspended in Et2O, stirred for 30 min and the precipitate was filtered off and dried to give 4-chloro-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3-one (4.91 g, 98% purity, yield 82%) as a light brown solid.

1H NMR (400 MHz, CDCl ₃ ): δ 7.34 (s, 3H), 7.16-7.12 (m, 2H), 6.95-6.91 (m, 1H), 3.91 ( s, 3H), 3.89 (s, 3H), 2.38 (s, 3H).

Example 13 2-[2-(3,4-Dimethoxyphenyl)-6-methyl-3-oxopyridazine-4-carbonyl]cyclohexane-1,3dione.

0.

Method A

A pressure reactor (100 mL) was charged with 4-bromo-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3one (3.00 g, 8.9 mmol), freshly purified 1,3-cyclohexadione (1.31 g, 11.6 mmol), palladium acetate (0.00204 g, 0.00890 mmol) and Dpephos (0.00489 g, 0.0890 mmol). The system was purged with argon and then triethylamine (2.51 ml, 17.8 mmol) and acetonitrile (12.5 ml) were added. The reaction mixture was stirred at 10 bar CO at 60° C. for 4 hours. After purging with Ar and cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was taken up in DCM (100 ml) and washed with 1 M HCl (75 ml). Water the phase was extracted with DCM (2x100 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to give crude 2-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxopyridazine-4-carbonyl]cyclohexane1,3-dione (3.858 g) in the form of yellow-brown foam. Quantitative NMR analysis using trimethoxybenzene as standard showed a purity of 81.7% (chemical yield 92%). This material was suspended in EtOH (7.5 ml), heated to reflux and stirred for 30 min to obtain a clear solution. After cooling to ambient temperature, the resulting precipitate was filtered off, washed on the filter with a small amount of Et ₂ O and dried under high vacuum to give 2-[2-(3,4-dimethoxyphenyl)-6-methyl-3oxopyridazine-4-carbonyl]cyclohexane- 1,3-dione (2.819 g, 99.2% purity, 82% practical yield) as a bright yellow solid.

¹ H NMR (400 MHz, CDCl3): δ 16.15 (s, 1H), 7.15-7.11 (m, 1H), 7.10-7.08 (m, 2H), 6.91 ( d, J=8.4 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 2.72 (t, J=6.2 Hz, 2H), 2.48- 2.43 (m, 2H), 2.41 (s, 3H), 2.04 (quin, J=6.4 Hz, 2H).

Method B

A pressure vessel was charged with 4-bromo-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3-one (0.200 g, 0.603 mmol), 1,3-cyclohexanedione (0.102 g, 0.905 mmol), Pd(OAc ) ₂ (0.00276 g, 0.0121 mmol) and bis(1adamantyl)butylphosphane (0.00606 g, 0.0169 mmol). The system was purged with argon, then diisopropylethylamine (0.21 ml, 1.21 mmol) and acetonitrile (2.5 ml) were added. The reaction mixture was stirred at 10 bar CO at 80° C. for 18 hours. After cooling to ambient temperature and purging with argon, the reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure, the residue was dissolved in dichloromethane and washed with aq. saturated NH4Cl solution. The aqueous phase was extracted with dichloromethane (2x), the combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 2-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxopyridazine-4-carbonyl] cyclohexane-1,3-dione (0.2684 g) as a yellow foam. Quantitative NMR analysis using trimethoxybenzene as internal standard showed a purity of 57.8% (chemical yield 67%).

Method C.

A pressure vessel was charged with 4-chloro-2-(3,4-dimethoxyphenyl)-6-methylpyridazin-3-one (0.200 g, 0.698 mmol), 1,3-cyclohexanedione (0.103 g, 0.91 mmol), Pd (OAc) ₂ (0.0032 g, 0.014 mmol) and 1,4-bis(dicyclohexylphosphino)-butane (0.0064 g, 0.014 mmol). The system was purged with argon, then triethylamine (0.20 ml, 1.4 mmol) and acetonitrile (2.5 ml) were added. The reaction mixture was stirred at 10 bar CO at 80° C. for 18 hours. After cooling to ambient temperature and purging with argon, the reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure, the residue was dissolved in dichloromethane and washed with aq. saturated NH4Cl solution. The aqueous phase was extracted with dichloromethane (2x), the combined organic layers

- 14 040702 was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain

2-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxopyridazine-4-carbonyl]cyclohexane-1,3-dione (0.295 g) as a brown foam. Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 49% (chemical yield 54%).

The following compounds were prepared using method A.

Example 14 2-[2-(4-Methoxyphenyl)-6-methyl-3-oxopyridazine-4-carbonyl]cyclohexane-1,3-dione

The crude 2-[2-(4-methoxyphenyl)-6-methyl-3-oxopyridazine-4-carbonyl]cyclohexane-1,3-dione (0.541 g) was obtained as a yellow foam. Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 82% (chemical yield 95%).

¹ H NMR (400 MHz, CDCla): δ 16.14 (br s, 1H), 7.54-7.46 (m, 2H), 7.09 (s, 1H), 6.99-6.93 (m, 2H), 3.83 (s, 3H), 2.73 (t, J=6.2Hz, 2H), 2.47 (t, J=5.9Hz, 2H), 2.41 ( s, 3H), 2.10-1.99 (m, 2H).

Example 15 2-[6-Methyl-3-oxo-2-[4-(trifluoromethyl)phenyl]pyridazine-4-carbonyl]cyclohexane-1,3dione.

The crude 2-[6-methyl-3-oxo-2-[4-(trifluoromethyl)phenyl]pyridazine-4-carbonyl]cyclohexane1,3-dione (0.531 g) was obtained as an orange foam. Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 76% (chemical yield 86%).

¹ H NMR (400 MHz, CDCl ₃ ): δ 16.15 (s, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.8 Hz, 2H), 7.10 (s, 1H), 2.75 (t, J=6.4 Hz, 2H), 2.48 (t, J=6.6 Hz, 2H), 2.43 (s, 3H), 2.10-2.03 (m, 2H).

Example 16 4-[5-(2,6-Dioxocyclohexanecarbonyl)-3-methyl-6-oxopyridazin-1-yl]benzonitrile

The crude 4-[5-(2,6-dioxocyclohexanecarbonyl)-3-methyl-6-oxopyridazin-1-yl]benzonitrile (0.482 g) was obtained as a yellow foam. Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 50% (chemical yield 58%).

¹ H NMR (400 MHz, CDCl3): δ 16.16 (s, 1H), 7.85-7.82 (m, 2H), 7.76-7.72 (m, 2H), 7.08 ( s, 1H), 2.76 (t, J=6.2 Hz, 2H), 2.49 (m, 2H), 2.43 (s, 3H), 2.11-2.03 (m, 2H ).

- 15 040702

Example 17 2-[6-Methyl-3-oxo-2-(p-tolyl)pyridazine-4-carbonyl]cyclohexane-1,3-dione

The crude 2-[6-methyl-3-oxo-2-(p-tolyl)pyridazine-4-carbonyl]cyclohexane-1,3-dione (0.531 g) was obtained as a green foam. Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 81% (chemical yield 92%).

'H NMR (400 MHz, CDC1 ₃ ): δ 16.13 (s, 1H), 7.47-7.43 (m, 2H), 7.25 (d, J=8.1 Hz, 2H), 7.10 (s, 1H), 2.73 (t, J=6.4 Hz, 2H), 2.47 (t, J=6.4 Hz, 2H), 2.41 (s, 3H), 2.38 (s, 3H), 2.09-2.01 (m, 2H).

Example 18 2-[6-Methyl-3-oxo-2-(m-tolyl)pyridazine-4-carbonyl]cyclohexane-1,3-dione

The crude 2-[6-methyl-3-oxo-2-(m-tolyl)pyridazine-4-carbonyl]cyclohexane-1,3-dione (0.528 g) was obtained as a yellow foam. Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 83% (chemical yield 94%).

'n NMR (400 MHz, CDCI3): δ 16.14 (s, 1H), 7.39-7.31 (m, 2H), 7.18 (d, J=6.6 Hz, 2H), 7 .10 (s, 1H), 2.73 (t, J=6.4 Hz, 2H), 2.48 (t, J=6.4 Hz, 2H), 2.42 (s, 3H), 2 .40 (s, 3H), 2.10-2.01 (m, 2H).

Example 19 2-[6-Methyl-3-oxo-2-(o-tolyl)pyridazine-4-carbonyl]cyclohexane-1,3-dione

The crude 2-[6-methyl-3-oxo-2-(o-tolyl)pyridazine-4-carbonyl]cyclohexane-1,3-dione (0.525 g) was obtained as a yellow foam. Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 80% (chemical yield 95%).

'n NMR (400 MHz, CDCI3): δ 16.03 (br s, 1H), 7.34-7.24 (m, 4H), 7.17 (s, 1H), 2.71 (t, J =6.2Hz, 2H), 2.46(t, J=6.2Hz, 2H), 2.41(s, 3H), 2.23(s, 3H), 2.08-1.99 (m, 2H).

Example 20 N-[4-[5-(2,6-dioxocyclohexanecarbonyl)-3-methyl-6-oxopyridazin-1-yl]phenyl]acetamide.

The crude N-[4-[5-(2,6-dioxocyclohexanecarbonyl)-3-methyl-6-oxopyridazin-1 yl]phenyl]acetamide (0.545 g) was obtained as a yellow foam. Quantitative NMR analysis using

Claims (14)

trimethoxybenzene as an internal standard showed a purity of 65% (chemical yield 83%). 1H NMR (400 MHz, CDCl ₃ ): δ 16.19 (br s, 1H), 7.59-7.47 (m, 4H), 7.09 (s, 1H), 2.74 (t, J =6.2Hz, 2H), 2.47 (t, J=6.6 Hz, 2H), 2.41 (s, 3H), 2.14 (s, 3H), 2.09-2.01 (m, 2H). Example 21 2-(2,6-Dimethyl-3-oxopyridazine-4-carbonyl)cyclohexane-1,3-dione ₀ ΑγΑ ₀ Y) ⁰ I The crude 2-(2,6-dimethyl-3-oxopyridazine-4-carbonyl)cyclohexane-1,3-dione (0.586 g) was obtained as a yellow gum. Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 78% (chemical yield 89%). 1H NMR (400 MHz, CDCl ₃ ): δ 16.16 (s, 1H), 7.04 (s, 1H), 3.74 (s, 1H), 2.75 (t, J=6.2 Hz , 2H), 2.49 (t, J=6.6 Hz, 2H), 2.35 (s, 3H), 2.11-2.03 (m, 2H). Example 22 2-(2-Butyl-6-methyl-3-oxopyridazine-4-carbonyl)cyclohexane-1,3-dione (ΥγΎ vY° ^N 'n^o The crude 2-(2-butyl-6-methyl-3-oxopyridazine-4-carbonyl)cyclohexane-1,3-dione (0.559 g) was obtained as a yellow gum. Quantitative NMR analysis using trimethoxybenzene as internal standard showed a purity of 73% (chemical yield 83%). 1H NMR (400 MHz, CDCl ₃ ): δ 16.16 (s, 1H), 7.01 (s, 1H), 4.10 (t, J=7.3, 2H), 2.73 (t, J=6.2, 2H), 2.48 (t, J=6.6 Hz, 2H), 2.35 (s, 3H), 2.11-2.02 (m, 2H), 1.81 -1.71 (m, 2H), 1.44-1.32 (m, 2H), 0.94 (t, J=7.3 Hz, 3H). Example 23 2-(3-Methyl-6-oxo-1H-pyridazine-5-carbonyl)cyclohexane-1,3-dione Ύο H The crude 2-(3-methyl-6-oxo-1H-pyridazine-5-carbonyl)cyclohexane-1,3-dione (1.480 g) was obtained as a beige foam. Quantitative NMR analysis using trimethoxybenzene as an internal standard showed a purity of 65% (chemical yield 79%). 1H NMR (400 MHz, CDCl ₃ ): δ 16.10 (br s, 1H), 11.44 (br s, 1H), 7.09 (s, 1H), 2.80-2.69 (m, 2H), 2.55-2.45(m, 2H), 2.35(s, 3H), 2.12-2.03(m, 2H). CLAIM 1. Process for the preparation of a compound of formula (I) where R ¹ is selected from the group consisting of hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ haloalkyl, C 1 -C 3 alkoxy-C ₁ -C ₃ -alkyl-, C ₁ -C ₃ -alkoxy-C ₂ -C ₃ -alkoxy-Cl-C ₃ -alkyl-, C ₆ -C ₁₀ -aryl and 5- or 6-membered heteroaryl, where heteroaryl contains from one to three heteroatoms, each of which is independently selected from the group , consisting of oxygen, nitrogen and sulfur, and where the aryl and heteroaryl components may be optionally substituted with one or more substituents selected from the group consisting of halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₃ -alkoxy, cyano and nitro; R ² is C ₁ -C ₆ -αkyl or C ₃ -C ₆ -cycloalkyl; A ¹ is selected from the group consisting of O, C(O) and (CR ⁷ R ⁸ ); each of R ⁴ , R ⁶ , R ⁷ and R ⁸ is independently selected from the group consisting of hydrogen and C1-C4 alkyl; and R ³ and R ⁵ are each independently selected from the group consisting of hydrogen and C 1 -C ₄ alkyl, or together they may form a C ₁ -C ₃ alkylene chain, the method comprising reacting a compound of formula (II) where X is halogen, with a compound of formula (III) where A ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ are defined for formula (I) above, in a reaction medium containing (i) a palladium catalyst; (ii) a suitable phosphine ligand or salt of a phosphine ligand; (iii) a suitable basis; and (iv) carbon monoxide, to give a compound of formula (I). 2. The method of claim 1 wherein R ¹ is an optionally substituted heteroaryl substituted with one or more substituents selected from the group consisting of halo, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ - C ₃ -alkoxy, cyano and nitro. 3. The method according to claim 1, where R ¹ represents an optionally substituted phenyl substituted with one or more substituents selected from the group consisting of halogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ - C ₃ -alkoxy, cyano and nitro. 4. The method according to claim 3, where R ¹ represents 3,4-dimethoxyphenyl. 5. The method according to any one of the previous paragraphs, where R ² represents methyl. 6. A method according to any one of the preceding claims, wherein X is selected from the group consisting of Br, Cl and I. 7. The method according to any of the previous paragraphs, where X represents Br. 8. The method according to any one of the preceding claims, wherein A ¹ is CR7R ⁸ and R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen. 9. The method according to any one of the preceding claims, wherein the reaction medium further comprises (v) a solvent. 10. The method of claim 9 wherein the solvent is acetonitrile. 11. Compound of formula (IIa1a) - 18 040702 12. Process for the preparation of a compound of formula (Ilala) comprising carrying out the reaction of a compound of formula (X) Il Τ (X) v. R ⁹ where R ⁹ is selected from the group consisting of Cl, Br and I, with a compound of formula (XI) SH - o (XI). 13. The method of claim 12 wherein compound (X) and compound (XI) are reacted using a photochemically catalyzed procedure. 14. Compound of formula (X) \ / ^Br Ύ A ^(X) R ⁹ where R ⁹ is selected from the group consisting of C1, Br and I. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2