RU2778306C1 - Method for preparation of 4-aminopyridines - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: group of inventions relates to organic chemistry and includes a method for obtaining dichloropyridazinamine compounds of formulas IVa, IVb, or mixtures thereof, a method for obtaining a pyridazinamine compound of formula V, or its salt, or tautomer, a method for obtaining a compound of formula VII, or its stereoisomer, or salt, or tautomer, as well as a mixture of intermediate dichloropyridazinamine compounds of formulas IVa and IVb for the preparation of a pyridazinamine compound of formula V. A method for producing (a) a dichloropyridazinamine compound of formula IVa, or its salt, or tautomer, or (b) a dichloropyridazinamine compound of formula IVb, or its salt, or tautomer, or (c) a mixture of (a) and (b) involves the interaction of a compound of formula III with ethylamine or its salt. The method additionally does not necessarily include a stage of obtaining a trichloropyridazine compound of formula III by reacting a compound of formula II with POCl₃. The method for obtaining a pyridazinamine compound of formula V, or its salt, or tautomer, includes a stage for obtaining a dichloropyridazinamine compound of formula IVa, or IVb, or their salt, or tautomer, or a mixture, by the above method. Then, (a) the dichloropyridazinamine compound of formula IVa, or its salt, or tautomer, or (b) the dichloropyridazinamine compound of formula IVb, or its salt, or tautomer, or (c) a mixture of (a) and (b) interact with hydrogen in the presence of a hydrogenation catalyst to obtain a compound of formula V. A method for obtaining a compound of formula VII, or its stereoisomer, or salt, or tautomer, involves the interaction of a compound of formula V, or its salt, or tautomer obtained by the above method, with a compound of formula VI, or its stereoisomer, or salt, or tautomer. In compounds of formulas IVa, IVb, V and VII, R¹ is CH₂CH₃. In compounds of formulas VI, VII, the substituents R², R³, R^N, X¹ are as indicated in the claims.

EFFECT: an improved method for obtaining intermediate compounds of dichloropyridazinamine formulas IVa, IVb, or mixtures thereof, with high yields, using ethylamine as a nucleophile, carried out at a reaction temperature of no more than 100°C and reaction time of no more than 12 hours.

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Description

The present invention relates to a process for the preparation of a pyridazinamine compound of formula V according to the following reaction sequence:

In the above scheme and the following, step (I) is the conversion of mucochlorous acid I to a compound of formula II, step (II) is the conversion of a compound of formula II to a trichloropyridazine compound of formula III, step (III) is the conversion of a trichloropyridazine compound of formula III to a mixture of dichloropyridazine compounds of formulas IVa and IVb, and step (IV) is the conversion of a mixture of compounds of formulas IVa and IVb into a pyridazine compound of formula V. It should be noted that steps (II) and (III) can also be carried out by reaction in one vessel, as indicated by reference to steps (II)+(III) in the above scheme.

The obtained pyridazine-amine compounds of formula V can be reacted with compounds of formula VI, obtaining compounds of formula VII in accordance with the following reaction scheme,

Hereinafter, this reaction step is referred to as step (V).

Pyridazinamine compounds, especially pyridazinamine compounds with an amino group at the 4-position of the pyridazine moiety, are versatile intermediates for the preparation of fine chemicals derived from pyridazines, such as compounds in the field of pharmaceuticals and agrochemicals. For example, pyridazinamine compounds are at the center of the search for drugs that are, for example, useful in the treatment of Alzheimer's disease, depression, hypotension and anxiety. In addition, pyridazinamine compounds are multipurpose pesticide intermediates with a pyridazine component, such as 4-pyrazole-N-pyridazinamide compounds, which are known to be particularly useful in the control of invertebrate pests (see WO 2009/027393, WO 2010 /034737, WO 2010/034738, and WO 2010/112177).

For certain applications, pyridazinamine compounds are desirable which do not contain any substituents other than an amino substituent, especially pyridazinamine compounds which are not additionally substituted with halogen substituents, eg chlorine. However, chlorine substituents are often present in pyridazinamine compounds, as a typical starting material for the preparation of these compounds by a nucleophilic substitution reaction with an amine compound, which is 3,4,5-trichloropyridazine.

In view of the foregoing, there is a need for an efficient dehalogenation process by which dichloropyridazinamine compounds can be converted to pyridazinamine compounds. In particular, there is a need for a process that provides improved yields. In view of the subsequent transformations of the resulting pyridazinamines, it is additionally desirable to carry out the reaction without the addition of water.

It is known in the art that the dehalogenation of certain dichloropyridazinamine compounds can be carried out by a hydrogenation/dehalogenation reaction in the presence of hydrogen and a hydrogenation catalyst. It is contemplated in the art that this hydrogenation/dehalogenation of the pyridazinamine compounds is carried out in the presence of a base. In this regard, reference should be made to WO 2011/038572; Journal of Heterocyclic Chemistry, 21(5), 1389-92; 1984; WO 2009/152325; US 4,728,355; WO 2011/124524; WO2010/049841; WO2013/142269; US 6,258,822; and WO 2001/007436. For example, WO 2011/038572 describes the dehalogenation of a mixture of 3,5-dichloro-4-pyridazinamine and 5,6-dichloro-4-pyridazinamine by reacting the mixture with hydrogen in the presence of a hydrogenation catalyst (Pd/C) and a base (sodium hydroxide).

The reason for adding the base is to avoid reducing the activity of the catalyst due to the production of HCl in the reaction. This is explained by F. Chang et al. in Bull. Korean Chem. soc. 2011, 32(3), 1075, an article that relates to Pd-catalyzed dehalogenation of aromatic halides. It is described that the HCl produced by dechlorination tends to be absorbed on the activated carbon resulting in progressive Pd/C poisoning and that it is effective to add some base to remove the HCl. It is also described that conversions in dechlorination reactions can be increased in the presence of a base.

However, the addition of a base is disadvantageous, especially for the industrial process. First, the reaction requires an additional chemical, i.e. a base, which makes the process more complicated. Secondly, the presence of a base complicates the recycling of the catalyst. In particular, when filtering the hydrogenation catalyst from the reaction, the chloride salts produced by the reaction of the base with HCl must be further filtered, so that the filter cake contains both the catalyst and the chloride salt (eg, KCl and KHCO ₃ ). After that, an additional processing procedure is necessary to re-isolate the catalyst.

Thus, it is an object of the present invention to provide a process for the dehalogenation of dichloropyridazinamine compounds which is suitable for industrial use.

In particular, it is an object of the present invention to provide a process which does not require the addition of a base as an additional chemical and which provides the advantage that the hydrogenation catalyst can be reused after the reaction without purification. At the same time, it is certainly desirable to provide high process yields.

The above problem is solved using method A, as described later in this application and in independent claim 1 and in claims that directly or indirectly depend on it.

In a first aspect, therefore, the present invention relates to a process, hereinafter referred to as process A, for the preparation of a pyridazinamine compound of formula V, or a salt, tautomer, or N-oxide thereof.

which comprises the step of reacting (a) a dichloropyridazinamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazinamine compound of formula IVb or a salt, tautomer or N-oxide thereof, or (c) a mixture of (a) and (b )

with hydrogen in the presence of a hydrogenation catalyst,

where

R ¹ represents H, C ₁ -C ₂ -alkyl, or C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl.

It should be noted that the reaction step underlying method A corresponds to step (IV) in the above reaction scheme.

The inventors of the present invention have surprisingly found that the dehalogenation of dichloropyridazinamine compounds can be carried out in the absence of an HCl neutralizer, i.e. in the absence of a base or other chemical suitable for binding HCl, and that the desired product can still be obtained in high yield. The hydrogenation catalyst can be easily filtered out after the reaction and can be reused without purification.

It has also been found that the HCl neutralizer can be used advantageously after the hydrogenation catalyst has been removed, such that the hydrogen chloride is bound and will not be released in gaseous form.

If the HCl neutralizer is used after removal of the hydrogenation catalyst, it has been found to be advantageous when the HCl neutralizer is provided without water as this facilitates processing.

In addition, the inventors of the present invention have surprisingly found that the yields of dehalogenation of dichloropyridazinamine compounds depend on the nature of the amino substituent. In this regard, it has surprisingly been found that the reaction can be favorably carried out with dichloropyridazinamine compounds in which the amino group is an ethylamino group.

Also, dichloropyridazinamine compounds are versatile intermediates for the preparation of fine chemicals, pyridazine derivatives, such as compounds in the field of pharmaceuticals and agrochemistry. In particular, chlorine substituents allow further derivatizations of the pyridazine moiety, for example, the introduction of additional amino groups via a nucleophilic substitution reaction. Therefore, a wide variety of dichloropyridazinamine compounds are available, since not only can the amino group be reacted with, for example, an activated carboxylic acid derivative, but also chlorine substituents can be replaced by other substituents.

Thus, there is also a need for an efficient process for the preparation of dichloropyridazinamine compounds.

In addition, there is a need to provide dichloropyridazinamine compounds in which the amino group is an ethylamino group, since these compounds or mixtures thereof are of great interest as intermediates for the production of pesticides and drugs.

Typically, dichloropyridazinamine compounds are prepared using 3,4,5-trichloropyridazine as starting compounds by a nucleophilic substitution reaction with an amino compound.

For example, WO 2011/038572 describes the preparation of a mixture of 3,5-dichloro-4-pyridazinamine and 5,6-dichloro-4-pyridazinamine by reacting 3,4,5-trichloropyridazine with ammonia gas over a reaction time of 4 days. A similar reaction is also described in US 4,728,355, where the reaction is carried out in a sealed tube at a temperature of 120-130°C for five days. The reaction is carried out at 125° C. for 5 hours according to Tsukasa Kuraishi et al. (Journal of Heterocyclic Chemistry, 1964, vol. 1, pp. 42-47).

The above reaction conditions for this reaction already indicate that it is believed in the art that either long reaction times or high temperatures are necessary for a nucleophilic substitution reaction, both of which are unfavorable for commercial processes.

In addition, the preparation of dichloropyridazinamine compounds by reacting 3,4,5-trichloropyridazine with an amino compound other than ammonia appears to present additional problems.

WO 99/64402 describes the reaction of 3,4,5-trichloropyridazine with 3-amino-1-propanol as a nucleophile. Although the reaction is carried out in boiling ethanol, the yields are extremely low (only 47.7% crude product) and laborious crystallization work-up is necessary to isolate the desired reaction products.

WO 2012/098387 describes the reaction of 3,4,5-trichloropyridazine with 2-methylaminoethanol as a nucleophile. Although a secondary amine is used as the nucleophile, which is more nucleophilic than the primary amine, the reaction is not quantitative and routine work-up by column chromatography is required.

Donna L. Romero et al. (Journal of Medicinal Chemistry, 1996, vol. 39, no. 19, pp. 3769-3789) have described the reaction of 3,4,5-trichloropyridazine with isopropylamine as the nucleophile. In accordance with the information presented in the article, the reaction can be carried out in refluxed toluene, that is, at a temperature of approximately 110°C. In addition, chromatography is necessary for purification.

Similarly, WO 96/18628 describes an identical reaction wherein 3,4,5-trichloropyridazine and isopropylamine are heated at reflux in toluene for hours. Subsequently, column chromatography is necessary to isolate the desired 4-isopropylamino-3,5-dichloropyridazine compound.

Thus, processes for the preparation of dichloropyridazines, as described in the prior art, are either unprofitable in terms of reaction conditions, yields, and/or processing requirements.

In addition, another disadvantage of the methods described in the prior art is the fact that the irritating compound 3,4,5-trichloropyridazine must be prepared and processed as a starting compound. Solid form processing of 3,4,5-trichloropyridazine is extremely unfavorable on an industrial scale.

Thus, it is an object of the present invention to provide a process for the preparation of dichloropyridazinamine compounds which overcomes the disadvantages regarding reaction conditions, yields and/or processing requirements, as evident from the prior art, or disadvantages regarding the use of the irritant 3,4,5-trichloropyridazine as starting material. component.

In this regard, it is extremely interesting to provide a simple process that is suitable for industrial implementation and provides satisfactory yields, preferably yields of more than 90%.

The above problem is solved using method B, as described later in this application and in independent claim 12 and in claims that directly or indirectly depend on it.

Thus, in a second aspect, the present invention relates to a process, hereinafter referred to as process B, for preparing (a) a dichloropyridazinamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazinamine compound of formula IVb or a salt thereof, tautomer or N-oxide, or (c) mixtures of (a) and (b)

by reaction in one vessel, including the steps

interaction of a compound of formula II

reaction of the resulting crude reaction product with an amino compound R ¹ -NH ₂ or a salt thereof,

where R ¹ represents H, C ₁ -C ₂ -alkyl, or C ₂ -C ₂ -alkoxy-C ₂ -C ₂ -alkyl.

It should be noted that the one-pot reaction underlying Method B corresponds to steps (II)+(III) in the above reaction sequence.

Surprisingly, it has been found that it is not necessary to use 3,4,5-trichloropyridazine as starting compound in the process for preparing dichloropyridazinamine compounds. Instead, 3,4,5-trichloropyridazine can be prepared in situ in a one-pot reaction with a compound of formula II as starting material. Thereafter, the in situ formed 3,4,5-trichloropyridazine is directly reacted with an amine compound to give the desired dichloropyridazinamine compounds.

This method is extremely advantageous for safety purposes since the irritant 3,4,5-trichloropyridazine compound does not need to be isolated and processed. This makes the process more suitable for industrial applications. In addition, the method is more economical and suitable for implementation on a larger scale.

Additionally, it has been found that extremely high yields of dichloropyridazinamine compounds can be obtained using the above described process, whereby severe reaction conditions are not necessary for the reaction of the in situ formed 3,4,5-trichloropyridazine with an amine compound. Thanks to the high yields, labor-intensive processing can also be avoided.

The above problem is also solved using method C, as described later in this application and in independent claim 13 and claims that directly or indirectly depend on it.

Therefore, in a third aspect, the present invention relates to a process, hereinafter referred to as process C, for the preparation of (a) a dichloropyridazinamine compound of formula IVa, or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazinamine compound of formula IVb, or a salt, tautomer thereof or N-oxide, or (c) mixtures of (a) and (b)

which includes the step of reacting a trichloropyridazine compound of formula III

with an amino compound R ¹ -NH ₂ or a salt thereof,

where R ¹ is CH ₂ CH ₃ ,

and wherein the method optionally further comprises the step of preparing a trichloropyridazine compound of formula III

by reacting a compound of formula II

with POCl ₃ .

It should be noted that the reaction step underlying Method C is covered by step (III) in the above reaction sequence. Optionally, step (II) of the above reaction sequence is also carried out.

Surprisingly, it has been found that the process for preparing dichloropyridazinamine compounds is extremely advantageous when ethylamine is used as the nucleophile in the nucleophilic substitution reaction. Although the prior art contemplates severe reaction conditions or at least long reaction times for nucleophilic substitution reactions, the inventors of the present invention have found that moderate reaction conditions with reaction temperatures of, for example, no more than 100° C. and reaction times , not more than 12 hours, is sufficient to provide the desired dichloropyridazineethylamines in high yields, and without laborious processing.

In a fourth aspect, the present invention provides a dichloropyridazinamine compound of formula IVa or a salt, tautomer or N-oxide thereof;

where R ¹ represents CH ₂ CH ₃ ;

or a dichloropyridazinamine compound of formula IVb or a salt, tautomer or N-oxide thereof,

where R ¹ represents CH ₂ CH ₃ .

Furthermore, the present invention relates to a mixture of a dichloropyridazinamine compound of formula IVa or a salt, tautomer or N-oxide thereof and a dichloropyridazinamine compound of formula IVb or a salt, tautomer or N-oxide thereof as defined above.

As already mentioned above, these compounds are extremely versatile precursors for the production of chemicals such as compounds in the field of pharmaceuticals and agrochemistry. They can also be used advantageously in the hydrogenation/dehalogenation process as described herein.

In a fifth aspect, the present invention relates to a process for preparing a compound of formula VII* or its stereoisomer, salt, tautomer or N-oxide

which includes the step of reacting a pyridazinamine compound of formula V or a salt, tautomer or N-oxide thereof

with a compound of formula VI* or its stereoisomer, salt, tautomer or N-oxide

where

R ¹ is CH ₂ CH ₃ ; and where

R ² is CH ₃ , R ³ is H, R ⁴ is CH ₃ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ is CF ₃ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ is CH(CH ₃ ) ₂ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ is CHFCH ₃ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ is I-CN-cC ₃ H ₄ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ is 1-C(O)NH ₂ -cC ₃ H ₄ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ and R ⁵ together are CH ₂ CH ₂ CF ₂ CH ₂ CH ₂ , and R ⁶ is H;

and where

X ¹ is a leaving group which is preferably selected from halogen, N ₃ , p-nitrophenoxy, and pentafluorophenoxy, and particularly preferably is chlorine.

This method is hereinafter referred to as method D. It should be noted that the reaction step underlying method D is covered by step (V) in the above reaction sequence.

The method demonstrates that the pyridazinamine compounds, which can be obtained using the hydrogenation/dehalogenation process as described in this application, are important intermediates for the preparation of 4-pyrazole-N-pyridazinamide compounds, which are pesticides, for example, suitable for controlling invertebrate pests.

It should be understood that methods A, B, C, and D, as defined above, may optionally further include additional reaction steps of the reaction sequence indicated above.

For example, method A may optionally further include step (III) and optionally also step (II), where steps (II) and (III) can be performed separately or together as steps (II)+(III) in a single vessel reaction. Additionally, method A may optionally further include step (I). In addition, it is understood that method A may optionally further include step (V).

Method B may optionally further include step (I) and/or step (IV). Additionally, step (V) may optionally be carried out after step (IV).

Method C may optionally further comprise step (I) and/or step (IV). Additionally, step (V) may optionally be carried out after step (IV).

Method D may optionally further include one or more of the preceding steps (IV), (III), (II) or (I) as indicated in the above reaction sequence.

It is contemplated that the reaction steps of the above reaction sequences, which are preferably covered by Methods A, B, C, or D, may be carried out separately, ie with or without isolation of intermediates. It is particularly preferred that certain successive steps are carried out by single vessel reactions, such as in the case of steps (II)+(III).

In addition, it should be emphasized that each of the reaction steps can be carried out on an industrial scale. Preferably, the reactants also convert well and only slight deviations in yields are observed.

In connection with the above aspects of the present invention, the following definitions are given.

"Compounds according to the present invention" or "compounds according to the invention", i.e. compounds of formulas I, II, III, IVa, IVb, V, VI, and VII (and VI* and VII*), as defined in this application , include the compound(s), as well as their salts, tautomers or N-oxides, if the formation of these derivatives; and, if centers of chirality are present, which may be the case for compounds VI and VII, as well as compounds VI* and VII*, also their stereoisomers.

As used in this application, the term "pyridazinamine compound(s)" refers to compounds of formula V, ie pyridazine compounds with an amino group -NHR ¹ as a substituent in the 4th position of the pyridazine component. Thus, the pyridazinamine compounds according to the invention do not contain any additional substituents on the pyridazine ring.

As used herein, the term "dichloropyridazinamine compound(s)" embraces compounds of formula IVa or IVb, or a combination thereof, i.e., pyridazine compounds with an amino group -NHR ¹ as a substituent and two chlorine substituents, where the substituents are present at those positions of the pyridazine component, which is derived from formulas IVa and IVb.

As used in this application, the term "trichloropyridazinamine compound(s)" preferably refers to compounds of formula III, ie 3,4,5-trichloropyridazine.

Depending on the acidity or alkalinity and the reaction conditions, the compounds of the present invention may be present in the form of a salt. Such salts are typically prepared by reacting a compound with an acid if the compound has an alkaline functionality, such as an amine, or by reacting a compound with a base if the compound has an acidic functionality, such as a carboxylic acid group.

The cations which are derived from the base with which the compounds of the present invention are reacted are, for example, alkali metal cations M _a ⁺ , alkaline earth metal cations _Mea ²⁺ or ammonium cations NR ₄ ⁺ , where the alkali metals are preferably sodium, potassium or lithium and alkaline earth metal cations are preferably magnesium or calcium, and where the substituents R of the ammonium cation NR ₄ ⁺ are preferably independently selected from H, C ₁ -C ₁₀ -alkyl, phenyl and phenyl-C ₁ -C ₂ -alkyl . Suitable cations are in particular alkali metal ions, preferably lithium, sodium and potassium, alkaline earth metals, preferably calcium, magnesium and barium, and transition metals, preferably manganese, copper, zinc and iron, and also ammonium (NH ⁴⁺ ) and substituted ammonium, in which from one to four hydrogen atoms are replaced by C ₁ -C ₄ -alkyl, C ₁ -C ₄ -hydroxyalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, hydroxy-C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, phenyl or benzyl. Examples of substituted ammonium ions include methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trimethylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxyethylammonium, 2-(2-hydroxyethoxy)ethylammonium, bis(2-hydroxyethyl)ammonium, benzyltrimethylammonium and benzyltriethylammonium, in addition , phosphonium ions, sulfonium ions, preferably tri(C ₁ -C ₄ -alkyl)sulfonium, and sulfoxonium ions, preferably tri(C ₁ -C ₄ -alkyl) sulfoxonium.

The anions which are derived from the acid with which the compounds of the present invention are reacted are, for example, chloride, bromide, fluoride, hydrogen sulfate, sulfate, dihydrogen phosphate, hydrogen phosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and anions of C ₁ -C ₄ -monobasic carboxylic acids, preferably formate, acetate, propionate and butyrate.

Tautomers of the compounds of the present invention include keto-enol tautomers, imine-enamine tautomers, amide-imido acid tautomers, and others. The compounds of the present invention encompass every possible tautomer.

The term "N-oxide" refers to the form of the compounds of the present invention in which at least one nitrogen atom is in its oxidized form (as NO). N-oxides of the compounds according to the present invention can be obtained if the compounds contain a nitrogen atom, which may be oxylene. N-oxides can advantageously be prepared using standard methods, for example using the method described in Journal of Organometallic Chemistry 1989, 370, 17-31. However, it is preferred according to the invention if the compounds are not present in the form of N-oxides. On the other hand, under certain reaction conditions, it is not possible to avoid the formation of N-oxides, at least intermediately.

The term "stereoisomers" encompasses both optical isomers, such as enantiomers or diastereomers, the latter being due to the presence of more than one center of chirality in the molecule, as well as geometric isomers (cis/trans isomers). Depending on the nature of the substitution, the compounds of the present invention may have one or more centers of chirality, in which case they may be present as mixtures of enantiomers or diastereomers. The invention provides both pure enantiomers or diastereomers and mixtures thereof. Suitable compounds according to the invention also include all possible geometric stereoisomers (cis/trans isomers) and mixtures thereof.

The compounds according to the invention may be in solid form or liquid form or gaseous form. When present as solids, the compounds may be amorphous or may exist in one or more different crystalline states (polymorphs) which may have different macroscopic properties such as stability or exhibit different biological properties such as activities. The present invention includes both amorphous and crystalline compounds, mixtures of various crystalline states, as well as amorphous or crystalline salts thereof.

The organic components referred to in the variable definitions above are - like the term halogen - collective terms for individual listings of members of individual groups. The prefix C _n -C _m indicates in each case the possible number of carbon atoms in the group.

The term "halogen" means in each case fluorine, bromine, chlorine or iodine, in particular fluorine, chlorine or bromine.

The term "alkyl" as used herein and in the alkyl components of alkylamino, alkylcarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl and alkoxyalkyl denotes in each occurrence a straight or branched alkyl group which typically has from 1 to 10 carbon atoms, often from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms. Examples of the alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2- dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl.

The term "haloalkyl", as used in this application and in the haloalkyl components of haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylthio, haloalkylsulfonyl, haloalkylsulfinyl, haloalkoxy and haloalkoxyalkyl, means in each case a straight or branched alkyl group, which usually has from 1 to 10 carbon atoms, often from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, where the hydrogen atoms of this group are partially or completely replaced by halogen atoms. Preferred haloalkyl components are selected from C ₁ -C ₄ -haloalkyl, more preferably from C ₁ -C ₃ -haloalkyl or C ₁ -C ₂ -haloalkyl, in particular from C ₁ -C ₂ -fluoroalkyl, such as fluoromethyl, difluoromethyl, trifluoromethyl , 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and others.

The term "alkoxy", as used in this application, means in each case a straight or branched alkyl group, which is linked via an oxygen atom and usually has from 1 to 10 carbon atoms, often from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms. Examples of the alkoxy group are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, t-butyloxy, and others.

The term "alkoxyalkyl", as used in this application, refers to alkyl, usually containing from 1 to 10, often from 1 to 4, preferably from 1 to 2 carbon atoms, where 1 carbon atom carries an alkoxy radical, usually containing from 1 to 4 , preferably 1 or 2 carbon atoms, as defined above. Examples are CH ₂ OCH ₃ , CH ₂ -OC ₂ H ₅ , 2-(methoxy)ethyl, and 2-(ethoxy)ethyl.

The term "haloalkoxy", as used in this application, means in each case a straight or branched alkoxy group which has from 1 to 10 carbon atoms, often from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, where the hydrogen atoms of this groups are partially or completely replaced by halogen atoms, in particular fluorine atoms. Preferred haloalkoxy components will include C ₁ -C ₄ -haloalkoxy, in particular C ₁ -C ₂ -fluoroalkoxy, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2- trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy and others.

The term "alkylsulfonyl" (alkyl-S(=O) ₂ -) as used herein refers to a straight or branched saturated alkyl group which has 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms (=C ₁ -C ₄ -alkylsulfonyl), preferably from 1 to 3 carbon atoms, which is linked via the sulfur atom of the sulfonyl group at any position in the alkyl group.

The term "haloalkylsulfonyl", as used in this application, refers to an alkylsulfonyl group as defined above, where the hydrogen atoms are partially or completely replaced by fluorine, chlorine, bromine and/or iodine.

The term "alkylcarbonyl" refers to an alkyl group, as defined above, which is bonded via the carbon atom of the carbonyl group (C=O) to the rest of the molecule.

The term "haloalkylcarbonyl" refers to an alkylcarbonyl group as defined above, wherein the hydrogen atoms are partially or wholly replaced by fluorine, chlorine, bromine and/or iodine.

The term "alkoxycarbonyl" refers to an alkylcarbonyl group, as defined above, which is bonded via an oxygen atom to the rest of the molecule.

The term "haloalkoxycarbonyl" refers to an alkoxycarbonyl group as defined above, wherein the hydrogen atoms are partially or wholly replaced by fluorine, chlorine, bromine and/or iodine.

The term "alkenyl" as used herein means in each case a singly unsaturated hydrocarbon radical which has usually 2 to 10, often 2 to 6, preferably 2 to 4 carbon atoms, e.g. vinyl, allyl (2- propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, metallyl (2-methylprop-2-en-1-yl), 2-buten-1-yl, 3-buten- 1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1-yl, 2-ethylprop-2-en-1- or others.

The term "haloalkenyl", as used in this application, refers to an alkenyl group, as defined above, where the hydrogen atoms are partially or completely replaced by halogen atoms.

The term "alkynyl" as used herein means in each case a singly unsaturated hydrocarbon radical which has usually 2 to 10, often 2 to 6, preferably 2 to 4 carbon atoms, e.g. ethynyl, propargyl (2- propyn-1-yl), 1-propyn-1-yl, 1-methylprop-2-yn-1-yl), 2-butyn-1-yl, 3-butyn-1-yl, 1-pentyn-1- yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 1-methylbut-2-yn-1-yl, 1-ethylprop-2-yn-1-yl and others.

The term "haloalkynyl", as used in this application, refers to an alkynyl group, as defined above, where the hydrogen atoms are partially or completely replaced by halogen atoms.

The term "cycloalkyl", as used in this application, and in the cycloalkyl components of cycloalkoxy and cycloalkylthio, means in each case a monocyclic cycloaliphatic radical, which usually has 3 to 10 or 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "halocycloalkyl", as used in this application and in the halocycloalkyl components of halocycloalkoxy and halocycloalkylthio, denotes in each case a monocyclic cycloaliphatic radical, which usually has from 3 to 10 carbon atoms or from 3 to 6 carbon atoms, where at least one, for example 1, 2, 3, 4 or 5 hydrogen atoms are replaced by a halogen, in particular fluorine or chlorine. Examples are 1- and 2-fluorocyclopropyl, 1,2-, 2,2- and 2,3-difluorocyclopropyl, 1,2,2-trifluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 1- and 2-chlorocyclopropyl, 1,2-, 2,2- and 2,3-dichlorocyclopropyl, 1,2,2-trichlorocyclopropyl, 2,2,3,3-tetrachlorocyclopropyl, 1-,2- and 3-fluorocyclopentyl, 1,2-, 2 ,2-, 2,3-, 3,3-, 3,4-, 2,5-difluorocyclopentyl, 1-,2- and 3-chlorocyclopentyl, 1,2-, 2,2-, 2,3-, 3,3-, 3,4-, 2,5-dichlorocyclopentyl and others.

The term "cycloalkoxy" refers to a cycloalkyl group, as defined above, which is bonded via an oxygen atom to the rest of the molecule.

The term "cycloalkylalkyl" refers to a cycloalkyl group as defined above which is linked via an alkyl group such as a C ₁ -C ₅ alkyl group or a C ₁ -C ₄ alkyl group, in particular a methyl group (=cycloalkylmethyl), with the rest of the molecule.

The term "cycloalkenyl", as used in this application, and in the cycloalkenyl components of cycloalkenyloxy and cycloalkenylthio, means in each case a monocyclic singly unsaturated non-aromatic radical, which usually has 3 to 10, for example 3, or 4 or 5 to 10 carbon atoms , preferably from 3 to 8 carbon atoms. Examples of cycloalkenyl groups include cyclopropenyl, cycloheptenyl or cyclooctenyl.

The term "halocycloalkenyl", as used in this application and in the halocycloalkenyl components of halocycloalkenyloxy and halocycloalkenylthio, denotes in each case a monocyclic singly unsaturated non-aromatic radical which has usually 3 to 10, for example 3 or 4 or 5 to 10 carbon atoms , preferably from 3 to 8 carbon atoms, where at least one, for example 1, 2, 3, 4 or 5 hydrogen atoms, is replaced by a halogen, in particular fluorine or chlorine. Examples are 3,3-difluorocyclopropen-1-yl and 3,3-dichlorocyclopropen-1-yl.

The term "cycloalkenylalkyl" refers to a cycloalkenyl group as defined above which is linked via an alkyl group such as a C ₁ -C ₅ alkyl group or a C ₁ -C ₄ alkyl group, in particular a methyl group (=cycloalkenylmethyl), with the rest of the molecule.

The term "carbocycle" or "carbocyclyl" includes in general 3 to 12 membered, preferably 3 to 8 membered or 5 to 8 membered, more preferably 5 to 6 membered monocyclic , a non-aromatic ring containing 3 to 12, preferably 3 to 8 or 5 to 8, more preferably 5 or 6 carbon atoms. Preferably, the term "carbocycle" embraces cycloalkyl and cycloalkenyl groups as defined above.

The term "heterocycle" or "heterocyclyl" includes in general 3 to 12 members, preferably 3 to 8 members, or 5 to 8 members, more preferably 5 to 6 members, in particular 6-membered monocyclic heterocyclic non-aromatic radicals. Heterocyclic non-aromatic radicals usually include 1, 2, 3, 4, or 5, preferably 1, 2 or 3 heteroatoms selected from N, O and S as ring members, where S atoms as ring members can be represented as S , SO or SO ₂ . Examples of 5- to 6-membered heterocyclic radicals include saturated or unsaturated, non-aromatic heterocyclic rings such as oxiranil, oxetanyl, thietanyl, thietanyl S-oxide (S-oxothietanyl), thietanyl S-dioxide (S-dioxothietanyl), pyrrolidinyl, pyrrolinyl, pyrazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, thiolanyl, S-oxothiolanyl, S-dioxothiolanyl, dihydrothienyl, S-oxodihydrothienyl, S-dioxodihydrothienyl, oxazolidinyl, oxazolinyl, thiazolinyl, oxathiolanyl, piperidinyl, piperidinyl, piperidine dihydropyranyl, tetrahydropyranyl, 1,3- and 1,4-dioxanyl, thiopyranyl, S.oxothiopyranyl, S-dioxothiopyranyl, dihydrothiopyranyl, S-oxodihydrothiopyranyl, S-dioxodihydrothiopyranyl, tetrahydrothiopyranyl, S-oxotetrahydrothiopyranyl, S-dioxotetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, S -oxothiomorpholinyl, S-dioxothiomorpholinyl, thiazinyl and others. Examples for a heterocyclic ring also containing 1 or 2 carbonyl groups as ring members include pyrrolidin-2-onyl, pyrrolidin-2,5-dionyl, imidazolidin-2-onyl, oxazolidin-2-onyl, thiazolidin-2-onyl and other.

The term "hetaryl" includes monocyclic 5- to 6-membered heteroaromatic radicals containing as ring members 1, 2, 3, or 4 heteroatoms selected from N, O, and S. Examples of 5- to 6-membered heteroaromatic radicals include pyridyl, i.e. 2-, 3-, or 4-pyridyl, pyrimidinyl, i.e. 2-, 4-, or 5-pyrimidinyl, pyrazinyl, pyridazinyl, i.e. 3- or 4-pyridazinyl, thienyl, i.e. 2 - or 3-thienyl, furyl, i.e. 2-or 3-furyl, pyrrolyl, i.e. 2- or 3-pyrrolyl, oxazolyl, i.e. 2-, 3-, or 5-oxazolyl, isoxazolyl, i.e. 3-, 4-, or 5-isoxazolyl, thiazolyl, i.e. 2-, 3- or 5-thiazolyl, isothiazolyl, i.e. 3-, 4-, or 5-isothiazolyl, pyrazolyl, i.e. 1-, 3-, 4-, or 5-pyrazolyl, i.e. 1-, 2-, 4-, or 5-imidazolyl, oxadiazolyl, e.g. 2- or 5-[1,3,4]oxadiazolyl, 4- or 5-(1,2,3 -oxadiazol)yl, 3- or 5-(1,2,4-oxadiazol)yl, 2- or 5-(1,3,4-thiadiazol)yl, thiadiazolyl, e.g. 2- or 5-(1,3 ,4-thiadiazol)yl, 4- or 5-(1,2,3-thiadiazol)yl, 3- or 5-( 1,2,4-thiadiazol)yl, triazolyl, e.g. 1H-, 2H- or 3H-1,2,3-triazol-4-yl, 2H-triazol-3-yl, 1H-, 2H-, or 4H -1,2,4-triazolyl and tetrazolyl, i.e. 1H- or 2H-tetrazolyl. The term "hetaryl" also includes bicyclic 8- to 10-membered heteroaromatic radicals containing as ring members 1, 2, or 3 heteroatoms selected from N, O, and S, where the 5- to 6-membered heteroaromatic ring is conjugated with a phenyl ring or with a 5- to 6-membered heteroaromatic radical. Examples of a 5 to 6 membered heteroaromatic ring conjugated to a phenyl ring or to a 5 to 6 membered heteroaromatic radical include benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzoxazinyl, quinolinyl, isoquinolinyl, purinyl, 1,8-naphthyridyl, pteridyl, pyrido[3,2-d]pyrimidyl or pyridoimidazolyl, and others. These conjugated hetaryl radicals may be linked to the rest of the molecule via any ring atom of the 5- to 6-membered heteroaromatic ring, or via the carbon atom of the conjugated phenyl component.

The term "aryl" includes mono-, bi- or tricyclic aromatic radicals, usually having 6 to 14, preferably 6, 10, or 14 carbon atoms. Examples of aryl groups include phenyl, naphthyl and anthracenyl. Phenyl is preferred as the aryl group.

The terms "heterocyclyloxy", "hetaryloxy", and "phenoxy" refer to heterocyclyl, hetaryl, and phenyl that are linked via an oxygen atom to the rest of the molecule.

The terms "heterocyclylsulfonyl", "hetarylsulfonyl", and "phenylsulfonyl" refer to heterocyclyl, hetaryl and phenyl, respectively, which are linked via the sulfur atom of the sulfonyl group to the rest of the molecule.

The terms "heterocyclylcarbonyl", "hetarylcarbonyl", and "phenylcarbonyl" refer to heterocyclyl, hetaryl and phenyl, respectively, which are bonded via a carbonyl carbon atom (C=O) to the rest of the molecule.

The terms "heterocyclylalkyl" and "hetarylalkyl" refer to heterocyclyl or hetaryl, respectively, as defined above, which are linked via a C ₁ -C ₅ alkyl group or a C ₁ -C ₄ alkyl group, in particular a methyl group (=heterocyclylmethyl or hetarylmethyl, respectively), with the rest of the molecule.

The term "phenylalkyl" refers to phenyl which is bonded via a C ₁ -C ₅ alkyl group or a C ₁ -C ₄ alkyl group, especially a methyl group (=arylmethyl or phenylmethyl), to the rest of the molecule, examples include benzyl, 1-phenylethyl, 2-phenylethyl, etc.

The terms "alkylene" refer to alkyl, as defined above, which is a linker between the molecule and the substituent.

Preferred embodiments of the invention relating to methods A, B, C, and D according to the invention are described later in this application.

In general, the reaction steps carried out in methods A, B, C, and D, as described in more detail later in this application, are carried out in reaction vessels conventional for such reactions, the reactions are carried out in a continuous, semi-continuous or batch manner.

In general, preferred reactions will be carried out at atmospheric pressure. However, the reactions can also be carried out under reduced pressure.

The temperatures and duration of the reactions can vary within a wide range, which are known to the skilled person in the art from similar reactions. The temperatures often depend on the reflux temperature of the solvents. Other reactions are preferably carried out at room temperature, ie at about 25°C, or under ice cooling, ie at about 0°C. The completion of the reaction can be monitored using methods known to those skilled in the art, such as thin layer chromatography or HPLC.

Unless specifically stated otherwise, the molar ratios of the reactants used in the reactions are in the range from 0.2:1 to 1:0.2, preferably from 0.5:1 to 1:0.5, more preferably from 0.8:1 to 1:0.8. Preferably, equimolar amounts are used.

Unless specifically stated otherwise, the reactants may in principle be contacted with each other in any desired sequence.

One skilled in the art will recognize that if the reactants or reactants are sensitive to moisture, then the reaction should be carried out under a protective gas atmosphere, such as nitrogen, and dry solvents should be used.

The person skilled in the art also knows the best way to handle the reaction mixture after the end of the reaction.

In the following, preferred embodiments relating to method A according to the invention are presented. It is understood that the preferred embodiments indicated above and those to be illustrated below for method A according to the invention are preferred alone or in combination with each other.

As already indicated above, the present invention relates in a first aspect to process A for the preparation of a pyridazinamine compound of formula V or a salt, tautomer or N-oxide thereof.

which comprises the step of reacting (a) a dichloropyridazinamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazinamine compound of formula IVb or a salt, tautomer or N-oxide thereof, or (c) a mixture of (a) and (b )

with hydrogen in the presence of a hydrogenation catalyst,

where

R ¹ represents H, C ₁ -C ₂ -alkyl, or C ₂ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl.

The reaction step underlying process A corresponds to step (IV) in the above reaction sequence.

The reaction step (IV) can only be carried out in the presence of a hydrogenation catalyst.

As used in this application, the term "hydrogenation catalyst" encompasses heterogeneous and homogeneous hydrogenation catalysts, but preferably refers to heterogeneous catalysts. Platinum, palladium, rhodium and ruthenium are known in the art to form extremely active catalysts. Base metal catalysts such as nickel based catalysts (such as Raney nickel and Urushibara nickel) are economic alternatives. Preferred hydrogenation catalysts in accordance with the invention are presented later in the present description.

As a by-product of reaction step (IV), hydrogen chloride is formed.

Despite this, in a preferred embodiment of method A, the reaction is carried out in the absence of an HCl neutralizer. Surprisingly, it has been found that compounds of formula V are obtained in higher yields when no HCl neutralizer is present in the reaction mixture.

As used herein, the term "HCl neutralizer" refers to a chemical that is added to a reaction mixture to remove or deactivate hydrogen chloride (HCl). Preferred HCl neutralizers include bases, buffers, and ionic liquid precursors, which are defined in more detail below. Of particular interest is the ability of the HCl neutralizer to bind protons. Preferred HCl neutralizers are shown below.

Preferably, the term "HCl neutralizer" as used herein is intended to refer to a chemical that is added to the reaction mixture and which does not include reaction starting materials, ie compounds of formula (IVa) or (IVb).

Therefore, it is preferred if the reaction step (IV) is carried out in the absence of any further added chemical that acts as an HCl neutralizer.

Since the reaction step (IV) is preferably carried out in the absence of an HCl neutralizer, the formed HCl is still in the reaction mixture when the hydrogenation catalyst is removed.

Thus, in another preferred embodiment of Method A, the HCl neutralizer is added after removal of the hydrogenation catalyst. Preferably, the HCl neutralizer is provided without water. It has been found advantageous to keep the reaction product, ie the compounds of formula V, free of water to avoid loss of the compounds in the aqueous phase, allowing for easier handling, and to avoid the need to dry the compound before further reactions.

The HCl neutralizer, which is preferably added only after removal of the hydrogenation catalyst, may advantageously be selected from bases, buffers, ionic liquid precursors, and combinations thereof.

Bases include alkali metal and alkaline earth metal hydroxides, alkali metal and alkaline earth metal oxides, alkali metal and alkaline earth metal hydrides, alkali metal amides, alkali metal and alkaline earth metal carbonates, alkali metal bicarbonates, alkali metal alkyls, alkyl magnesium halides. , alkali metal and alkaline earth metal alcoholates, and nitrogen-containing bases, including tertiary amines, pyridines, bicyclic amines, ammonia, and primary amines.

Buffers include aqueous and non-aqueous buffers, and are preferably non-aqueous buffers. Preferred buffers include buffers based on acetate or formate, for example sodium acetate or ammonium formate.

Ionic liquid precursors include imidazoles.

In a preferred embodiment of Method A of the present invention, the HCl neutralizer is selected from the group consisting of bases including alkali metal and alkaline earth metal hydroxides, alkali metal and alkaline earth metal oxides, alkali metal and alkaline earth metal hydrides, alkali metal amides , alkali metal and alkaline earth metal carbonates, alkali metal bicarbonates, alkali metal alkyls, alkyl magnesium halides, alkali metal and alkaline earth metal alcoholates, nitrogen-containing bases including tertiary amines, pyridines, bicyclic amines, ammonia, and primary amines, and their combinations; buffers, including sodium acetate and/or ammonium formate; ionic liquid precursors, including imidazoles; and their combinations.

In one preferred embodiment, the HCl neutralizer contains at least one base.

In one particularly preferred embodiment, the base is selected from alkali metal and alkaline earth metal hydroxides, especially from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide.

In another particularly preferred embodiment, the base is selected from oxides of alkali metals and alkaline earth metals, in particular from the group consisting of lithium oxide, sodium oxide, calcium oxide, and magnesium oxide.

In another particularly preferred embodiment, the base is selected from alkali metal and alkaline earth metal hydrides, especially from the group consisting of lithium hydride, sodium hydride, potassium hydride, and calcium hydride.

In another particularly preferred embodiment, the base is selected from alkali metal amides, especially from the group consisting of lithium amide, sodium amide, and potassium amide.

In another particularly preferred embodiment, the base is selected from alkali metal and alkaline earth metal carbonates, especially from the group consisting of lithium carbonate and calcium carbonate.

In another particularly preferred embodiment, the base is selected from alkali metal bicarbonates, and preferably is sodium bicarbonate.

In another particularly preferred embodiment, the base is selected from alkali metal alkyls, in particular from the group consisting of methyllithium, butyllithium, and phenyllithium.

In another particularly preferred embodiment, the base is selected from alkylmagnesium halides, and is preferably methylmagnesium chloride.

In another particularly preferred embodiment, the base is selected from alkali metal and alkaline earth metal alcoholates, especially from the group consisting of sodium methanolate, sodium ethanolate, potassium ethanolate, potassium t-butanolate, and dimethoxymagnesium.

In another particularly preferred embodiment, the base is a tertiary amine, in particular trimethylamine, triethylamine, diisopropylethylamine, or N-methylpiperidine.

In another particularly preferred embodiment, the base is pyridine, including substituted pyridines such as collidine, lutidine, and 4-dimethylaminopyridine.

In another particularly preferred embodiment, the base is a bicyclic amine.

In another particularly preferred embodiment, the base is ammonia.

In another particularly preferred embodiment, the base is a primary amine, in particular ethylamine.

In the most preferred embodiment of method A according to the invention, the HCl neutralizer is potassium hydroxide or any of the above-defined carbonates.

The bases may be used in any equimolar amounts, in excess, or, if appropriate, as solvents.

In another preferred embodiment, the HCl neutralizer contains at least one buffer.

In a particularly preferred embodiment, the buffer is anhydrous sodium acetate or anhydrous ammonium formate.

In another preferred embodiment, the HCl neutralizer contains an ionic liquid precursor.

In a particularly preferred embodiment, the ionic liquid precursor is an imidazole compound which forms an ionic liquid upon reaction with HCl, which is set free in the hydrogenation/dehalogenation reaction. Thereafter, the non-polar organic phase containing the desired pyridazinamine compound can be easily separated from the newly formed ionic liquid.

As already mentioned above, any hydrogenation catalysts known in the art can be used for reaction step (IV), especially heterogeneous hydrogenation catalysts.

Preferred hydrogenation catalysts include platinum, palladium, rhodium, ruthenium, nickel, or cobalt on supports such as carbon.

In a preferred embodiment of Process A of the present invention, the hydrogenation catalyst is selected from the group consisting of supported platinum or palladium, Raney nickel, and Raney cobalt, and is preferably platinum or palladium on carbon.

Optionally, the catalyst may be doped with sulfur or selenium. This can improve the selectivity of the catalyst.

In a particularly preferred embodiment, the hydrogenation catalyst is preferably palladium or platinum on carbon, where the content of palladium or platinum is preferably in the range of 0.1 to 15% by weight, more preferably 0.5 to 10% by weight based on the material carrier.

In another particularly preferred embodiment, the amount of palladium or platinum used is from 0.001 to 1% by weight, preferably from 0.01 to 0.1% by weight, based on the starting material.

In one particularly preferred embodiment, the hydrogenation catalyst is palladium on carbon, where the palladium content is preferably in the range of 0.1 to 15% by weight, more preferably 0.5 to 10% by weight based on the support material. In addition, it is particularly preferred that the amount of palladium used in the reaction step (IV) is 0.001 to 1% by weight, preferably 0.01 to 0.1% by weight, based on the starting material. More preferably, 10% Pd/C is used in an amount of 0.01 to 0.1% by weight based on the weight of the starting material.

In another particularly preferred embodiment, the hydrogenation catalyst is platinum on carbon, where the platinum content is preferably 0.1 to 15% by weight, more preferably 0.5 to 10% by weight based on the support material. In addition, it is particularly preferred that the amount of platinum used in the reaction step (IV) is 0.001 to 1, preferably 0.01 to 0.1% by weight based on the starting material. More preferably, 10% Pt/C is used in an amount of 0.01 to 0.1% by weight based on the weight of the starting material.

In batch hydrogenation, the catalyst is preferably used in powder form. In continuous hydrogenation, the catalyst used on carbon support material is platinum or palladium.

After the reaction cycle, the catalyst can be filtered off and reused without noticeable loss of activity.

With respect to the starting materials in reaction step (IV), it should be noted that either (a) a dichloropyridazinamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazinamine compound of formula IVb or a salt, tautomer or N-oxide, or (c) a mixture of (a) and (b).

In a preferred embodiment of method A, a mixture of (a) and (b) is used.

The R ¹ substituent in the compounds of formulas IVa, IVb, and V is preferably selected from the group consisting of CH ₃ , CH ₂ CH ₃ , and CH ₂ OCH ₃ .

In a preferred embodiment of Method A, R ¹ in the compounds of formulas IVa, IVb, and V is CH ₂ CH ₃ .

In a particularly preferred embodiment of Method A, a mixture of (a) and (b) is used and R ¹ in the compounds of formulas IVa, IVb, and V is selected from the group consisting of CH ₃ , CH ₂ CH ₃ , and CH ₂ OCH ₃ , and preferably represents CH ₂ CH ₃ .

Soft reaction are preferred for reaction step (IV).

In a preferred embodiment, the applied hydrogen pressure is in the range of 0.1 to 10 bar, preferably in the range of 0.1 to 1 bar, more preferably in the range of 0.1 to 0.5 bar. Elevated pressures in the range of 0.6 bar to 10 bar, preferably 1 bar to 5 bar, can be advantageous if the starting material contains impurities in an amount of more than 2% by weight or more than 5% by weight.

In a preferred embodiment, the reaction temperature is maintained in the range of 20 to 100°C, preferably in the range of 20 to 65°C. It is preferred that the reaction mixture is heated to a temperature of 30 to 40° C. after the high pressure reactor, where the reaction is preferably carried out, is filled with hydrogen. However, since the hydrogenation reaction is exothermic, it may be necessary to subsequently cool the reaction mixture to maintain the temperature preferably below 60°C. Particularly preferred is a reaction temperature in the range of 50 to 60°C.

The reaction time can vary over a very wide range. Preferred reaction times are in the range of 1 hour to 12 hours, preferably in the range of 3 hours to 6 hours, such as 4 or 5 hours.

Suitable solvents include water and aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether; aromatic hydrocarbons such as toluene, o-, m- and n-xylene; halogenated hydrocarbons such as methylene chloride, chloroform and chlorobenzene; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol; C ₂ -C ₄ alkanediols such as ethylene glycol or propylene glycol; ether alkanols such as diethylene glycol; carboxylic acid esters such as ethyl acetate; N-methylpyrrolidone; dimethylformamide; and ethers, including open chain ethers and cyclic ethers, especially diethyl ether, methyl tert-butyl ether (MTBE), 2-methoxy-2-methylbutane, cyclopentylmethyl ether, 1,4-dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran, especially tetrahydrofuran, MTBE, and 2-methyltetrahydrofuran. Mixtures of these solvents can also be used.

Preferred solvents are protic solvents, preferably alcohols selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butaiol.

In a preferred embodiment, the solvent is a C ₁ -C ₄ alcohol, especially ethanol.

As can be seen above, method A may not only include the reaction step (IV), but also other reaction steps of the reaction sequence described above.

In particular, method A may optionally further comprise step (III) and optionally also step (II), where steps (II) and (PT) can be carried out separately or together as steps (II)+(III) in a single vessel reaction . Additionally, method A may optionally further include step (I). In addition, it is understood that method A may optionally further include step (V).

In one embodiment of Method A, the method further comprises reaction steps (II)+(III), i.e. the step of producing (a) a dichloropyridazinamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazinamine compound of formula IVb or its salt, tautomer or N-oxide, or (c) mixtures of (a) and (b)

by reaction in one vessel, including the steps

interaction of a compound of formula II

with POCl ₃ , and

reaction of the resulting crude reaction product with an amino compound R ¹ -NH ₂ or a salt thereof,

where R ¹ represents H, C ₁ -C ₂ -alkyl, or C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl.

As indicated above, the one-pot reaction is favorable because the intermediate trichloropyridazine compound of formula III, which is irritant, does not need to be isolated.

It is understood that (a) or (b) or a mixture of (a) and (b) can be obtained in steps (II)+(III).

In a preferred embodiment, a mixture of (a) and (b) is obtained.

The substituent R ¹ in the compounds of formulas IVa and IVb, and the amine compound R ¹ -NH ₂ are preferably selected from the group consisting of CH ₃ , CH ₂ CH ₃ , and CH ₂ OCH ₃ .

In a preferred embodiment, R ¹ in the compounds of formulas IVa and IVb, and the amine compound R ¹ -NH ₂ is CH ₂ CH ₃ .

In a particularly preferred embodiment, a mixture of (a) and (b) is obtained, and R ¹ in the compounds of formulas IVa and IVb, and the amine compound R ¹ -NH ₂ is selected from the group consisting of CH ₃ , CH ₂ CH ₃ , and CH ₂ OCH ₃ , and preferably is CH ₂ CH ₃ .

It is contemplated that the compound of formula II may also be present in the form of its pyridazone tautomer.

The reaction conditions for steps (II) and (III), which are carried out sequentially in the same vessel reaction as defined above, without isolating the intermediate compound of formula III, are defined in more detail below.

In an alternative embodiment of method A, the method further comprises a reaction step (III), i.e. the step of obtaining (a) a dichloropyridazinamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazinamine compound of formula IVb or a salt thereof, tautomer or N-oxide, or (c) mixtures of (a) and (b)

by reacting a trichloropyridazine compound of formula III

with an amino compound R ¹ -NH ₂ or a salt thereof,

where R ¹ represents H, C ₁ -C ₂ -alkyl, or C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl,

and where the method optionally further comprises a reaction step (II), i.e. a step for preparing a trichloropyridazine compound of formula III

by reacting a compound of formula II

with POCl ₃ .

According to this embodiment, the compound of formula III is isolated, which can be done, for example, by precipitation.

It is understood that (a) or (b) or a mixture of (a) and (b) can be obtained in steps (III).

In a preferred embodiment, a mixture of (a) and (b) is obtained.

The substituent R ¹ in the compounds of formulas IVa and IVb, and the amine compound R ¹ -NH ₂ are preferably selected from the group consisting of CH ₃ , CH ₂ CH ₃ , and CH ₂ OCH ₃ .

In a preferred embodiment, R ¹ in the compounds of formulas IVa and IVb, and the amine compound R ¹ -NH ₂ is CH ₂ CH ₃ .

In a particularly preferred embodiment, a mixture of (a) and (b) is obtained, and R ¹ in the compounds of formulas IVa and IVb, and the amine compound R ¹ -NH ₂ is selected from the group consisting of CH ₃ , CH ₂ CH ₃ , and CH ₂ OCH ₃ , and preferably is CH ₂ CH ₃ .

As already indicated above, it is understood that the compound of formula II may also be present in the form of its pyridazone tautomer.

The reaction conditions for steps (II) and (III), which also apply to the situation in which steps are carried out as steps (II)+(IIII) in a single vessel reaction, are defined hereinafter.

The reaction conditions for step (II) are preferably as follows.

In a preferred embodiment of reaction step (II), POCl ₃ is used in excess.

In another preferred embodiment, POCl ₃ is used in an amount of at least 1.5 mol per mol of the compound of formula II.

In one particularly preferred embodiment, POCl ₃ is used in an amount of 1.5 to 2.0 mol per mol of the compound of formula II.

In another particularly preferred embodiment, POCl ₃ is used in an amount of more than 2.0 to 10 mol per mol of the compound of formula II, preferably in an amount of from 4.0 to 6.0 mol, in particular in an amount of from 4.8 to 5 .2 mol per mol of the compound of formula II.

In yet another particularly preferred embodiment, POCl ₃ is used as solvent for the reaction step (II).

It is preferred that the reaction step (II) is carried out in the absence of a solvent.

It is further preferred that the reaction is carried out under a protective gas atmosphere, for example under a nitrogen atmosphere.

The reaction temperature may be in the range of 60°C to 130°C, preferably in the range of 100°C to 125°C.

The reaction time can vary over a very wide range, and is preferably in the range of 1 hour to 24 hours, preferably in the range of 1 hour to 5 hours, more preferably in the range of 1 hour to 2 hours.

After the reaction, excess POCl ₃ can be removed under reduced pressure. Thereafter, water is preferably added to the reaction mixture while cooling, so that the temperature preferably does not exceed 30°C.

The trichloropyridazine compound of formula III can be isolated as a precipitate from the aqueous phase, or by transferring the compound of formula III to the organic phase and removing the organic solvent.

Preferred organic solvents in this regard include dichloromethane, iso-butanol, ethyl acetate, and butyl acetate, especially butyl acetate.

With regard to the preparation and isolation of the trichloropyridazine compound of formula III, reference may be made to, for example, WO 2013/004984, WO 2014/091368, WO 99/64402, WO 2002/100352, and Russian Journal of Applied Chemistry, Vol. 77, No. 12 , 2004, pp. 1997-2000.

If a one-pot reaction procedure as defined above is carried out, then the step of isolating the trichloropyridazine compound of formula III can be omitted. Instead, trichloropyridazine is transferred to the organic phase and used directly in the next reaction step.

Preferred organic solvents in this connection include dichloromethane, iso-butanol, ethyl acetate and butyl acetate, especially butyl acetate.

The organic phase can optionally be washed with a solution of sodium hydroxide in water (eg 10% aqueous NAOH) and/or water before further use.

The reaction conditions for step (III) are preferably as follows.

Depending on the substituent R ¹ , the amine compound R ¹ -NH ₂ may be in gaseous or liquid or solid form. If the amine compound R ¹ -NH ₂ is in gaseous form, then it can be provided either as a solution or as a gas.

A particularly preferred amine compound is ethylamine, as already mentioned above.

Suitable solvents include protic solvents, preferably water or C ₁ -C ₄ alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butaiol, especially ethanol.

In one preferred embodiment, the solvent where the amine compound R ¹ -NH ₂ is provided is water. Suitable concentrations are in the range of 10 to 100% by weight based on the total weight of the solution, preferably in the range of 40 to 90% by weight, more preferably 60 to 80%, most preferably 66 to 72% by weight.

In a particularly preferred embodiment, the amine compound R ¹ -NH ₂ . is ethylamine and is provided as a solution in water at a concentration in the range of 60 to 80% based on the total weight of the solution, preferably 66 to 72% by weight.

It is an unexpected finding according to the present invention that the presence of water in the reaction mixture does not adversely affect the yields of the reaction step (III).

In another preferred embodiment, the amine compound R ¹ -NH ₂ . is provided in gaseous form and introduced into the reaction mixture by bubbling it into the solvent where the reaction step (III) will be carried out and where the trichloropyridazine compound of formula III may already be dissolved. In this regard, preferred solvents include protic solvents, preferably alcohols selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butaiol. A particularly preferred solvent is ethanol. In addition, preferred solvents in which the gaseous amine compound R1-NH ₂ can be dissolved for the reaction step (III) generally include toluene, THF, and ethanol.

It is preferred that an excess of the amine compound R ¹ -NH ₂ is used.

In a preferred embodiment, the amine compound R ¹ -NH ₂ is used in an amount of from 1.5 to 10 mol per mol of the compound of formula III, preferably in an amount of from 2.0 to 6.0 mol, in particular in an amount of from 2.0 to 3.0 mol per mol of compound of formula III.

Suitable reaction solvents include water and aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether; aromatic hydrocarbons such as toluene, o-, m- and n-xylene; halogenated hydrocarbons such as methylene chloride, chloroform and chlorobenzene; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol; C ₂ -C ₄ alkanediols such as ethylene glycol or propylene glycol; ether alkanols such as diethylene glycol; carboxylic acid esters such as ethyl acetate; N-methylpyrrolidone; dimethylformamide; and ethers, including open chain ethers and cyclic ethers, especially diethyl ether, methyl tert-butyl ether (MTBE), 2-methoxy-2-methylbutane, cyclopentylmethyl ether, 1,4-dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran, especially tetrahydrofuran, MTBE, and 2-methyltetrahydrofuran. Mixtures of these solvents can also be used.

It is particularly preferred that the reaction is carried out in a mixture of solvents in which the starting materials are provided, for example mixtures of water and butyl acetate.

Alternatively, it is particularly preferred that the reaction is carried out in protic solvents, preferably alcohols selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butaiol, especially ethanol, especially if the amine compound is provided in gaseous form. After that, the reaction step (III) will be carried out in this protic solvent, and optionally also the reaction step (IV) can be directly carried out then in a one-pot reaction, optionally using an excess of an amine compound as an HCl neutralizer.

The reaction can be carried out at temperatures ranging from 0°C to 140°C, preferably in the range from 25°C to 60°C, more preferably in the range from 30°C to 50°C.

With regard to the amine compound R ¹ -NH ₂ as defined herein, in particular the amine compound R ¹ -NH ₂ which is ethylamine, the following reaction temperatures are particularly preferred.

In one embodiment, the reaction stage (III) is carried out at a temperature of 100°C or less.

In another embodiment, the reaction stage (III) is carried out at a temperature of 80°C or less.

In another embodiment, the reaction stage (III) is carried out at a temperature of 70°C or less.

In another embodiment, the reaction stage (III) is carried out at a temperature of 60°C or less.

In one embodiment, the reaction stage (III) is carried out at a temperature of from 0°C to 100°C.

In another embodiment, the reaction stage (III) is carried out at a temperature of from 0°C to 80°C.

In another embodiment, the reaction stage (III) is carried out at a temperature of from 0°C to 70°C.

In another embodiment, the reaction stage (III) is carried out at a temperature of from 0°C to 60°C.

In a preferred embodiment, the reaction stage (III) is carried out at a temperature of from 20°C to 80°C.

In another preferred embodiment, the reaction stage (III) is carried out at a temperature of from 20°C to 70°C.

In another preferred embodiment, the reaction stage (III) is carried out at a temperature of from 20°C to 60°C.

In a particularly preferred embodiment, the reaction stage (III) is carried out at a temperature of from 25°C to 60°C.

The reaction time will vary over a wide range, for example, in the range from 1 hour to 4 days. Preferably, the reaction time is in the range from 1 hour to 24 hours, in particular from 1 hour to 12 hours. More preferably, the reaction time is in the range of 1 hour to 5 hours, preferably 3 hours to 4 hours.

For the reaction step (III), reference can also be made to US 4,728,355.

As already stated above, method A may optionally further comprise step (I) to provide a compound of formula II.

In one embodiment of method A, the method comprises, in addition to steps (II) and (III), either carried out separately or as a reaction in the same vessel, also step (I), i.e. the method further comprises the step of obtaining a compound of formula II

by the reaction of mucochlorous acid I

with hydrazine or its salt.

The reaction conditions for step (III) are preferably as follows.

The reactants are preferably provided in similar amounts, for example in a molar ratio of 1.5:1 to 1:1.5, preferably in equimolar amounts.

The hydrazine is preferably provided in the form of a salt, preferably as hydrazine sulfate.

Suitable solvents include protic solvents such as water.

The reaction mixture is preferably heated to 100° C. until a precipitate forms.

For further details, reference is made to US 4,728,355.

As already mentioned above, method A may optionally further include step (V).

In one embodiment of Method A, the method further comprises step (V), i.e. the method further comprises the step of converting a pyridazinamine compound of formula V, or a salt, tautomer, or N-oxide thereof, to a compound of formula VII, or a stereoisomer, salt, tautomer, or N-oxide thereof

by reaction of a pyridazinamine compound of formula V or a salt, tautomer or N-oxide thereof

with a compound of formula VI or its stereoisomer, salt, tautomer or N-oxide

where R ¹ represents H, C ₁ -C ₂ -alkyl, or C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl,

and where

R ² is H, halogen, CN, NO ₂ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ - alkenyl, or C ₂ -C ₁₀ -alkynyl, where at least 3 of the last indicated radicals may be unsubstituted, may be partially or fully halogenated or may bear 1, 2 or 3 identical or different substituents R ^x , or

OR ^a , SR ^a , C(Y)R ^b , C(Y)OR ^c , S(O)R ^d , S(O) ₂ R ^d , NR ^e R ^f , C(Y)NR ^g R ^h , heterocyclyl , hetaryl, C ₃ -C ₁₀ -cycloalkyl, C ₃ -C ₁₀ -cycloalkenyl or phenyl, where the last five indicated radicals may be unsubstituted or may carry 1, 2, 3, 4 or 5 identical or different substituents selected from the radicals R ^y and R ^x ;

R ³ is H, halogen, CN, NO ₂ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl, or C ₂ -C ₁₀ -alkynyl, where at least 3 of the last indicated radicals may be unsubstituted, may be partially or fully halogenated or may bear 1, 2 or 3 identical or different substituents R ^x , or

OR ^a , SR ^a , C(Y)R ^b , C(Y)OR ^c , S(O)R ^d , S(O) ₂ R ^d , NR ^e R ^f , C(Y)NR ^g R ^h , heterocyclyl , hetaryl, C ₃ -C ₁₀ -cycloalkyl, C ₃ -C ₁₀ -cycloalkenyl or phenyl, where the last five indicated radicals may be unsubstituted or may carry 1, 2, 3, 4 or 5 identical or different substituents selected from the radicals R ^y and R ^x ;

R ^N is H, CN, NO ₂ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl, or C ₂ -C ₁₀ -alkynyl, where the last three radicals indicated may be unsubstituted, may be partially or completely halogenated or may carry 1, 2 or 3 identical or different substituents R ^x , or

OR ^a , SR ^a , C(Y)R ^b , C(Y)OR ^c , S(O)R ^d , S(O) ₂ R ^d , NR ^e R ^f , C(Y)NR ^g R ^h , S (O) _m NR ^e R ^f , C(Y)NR ⁱ NR ^e R ^f , C ₁ -C ₅ -alkylene-OR ^a , C ₁ -C ₅ -alkylene-CN, C ₁ -C ₅ -alkylene-C (Y)R ^b , C ₁ -C ₅ -alkylene-C(Y)OR ^c , C ₁ -C ₅ -alkylene-NR ^e R ^f , C ₁ -C ₅ -alkylene-C(Y)NR ^g R ^h , C ₁ -C ₅ -alkylene-S(O) _m R ^d , C ₁ -C ₅ -alkylene-S(O) _m NR ^e R ^f , C ₁ -C ₅ -alkylene-NR ⁱ NR ^e R ^f , heterocyclyl, hetaryl, C ₃ -C ₁₀ -cycloalkyl, C ₃ -C ₁₀ -cycloalkenyl, heterocyclyl-C ₁ -C ₅ -alkyl, hetaryl-C ₁ -C ₅ -alkyl, C ₃ -C ₁₀ -cycloalkyl-C ₁ -C ₅ -alkyl, C ₃ -C ₁₀ -cycloalkenyl-C ₁ -C ₅ -alkyl, phenyl-C ₁ -C ₅ -alkyl, or phenyl, where the rings of the last ten indicated radicals may be unsubstituted or may carry 1, 2 , 3, 4 or 5 identical or different substituents R ^y ;

and where

R ^a , R ^b , R ^c are each independently selected from H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkylmethyl , C ₃ -C ₆ -halocycloalkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -haloalkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, heterocyclyl , heterocyclyl-C ₁ -C ₄ -alkyl, phenyl, hetaryl, phenyl-C ₁ -C ₄ -alkyl, and hetaryl-C ₁ -C ₄ -alkyl, where the ring in the last six indicated radicals may be unsubstituted or may carry 1 , 2, 3, 4, or 5 substituents, which are independently selected from halogen, CN, NO ₂ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy , and C ₁ -C ₄ haloalkoxy;

R ^d is selected from C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkylmethyl, C ₃ -C ₆ -halocycloalkyl, C ₂ -C ₄ - alkenyl, C ₂ -C ₄ -haloalkenyl, C ₂ -C ₄ -alkynyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, heterocyclyl, heterocyclyl-C ₁ -C ₄ -alkyl, phenyl, hetaryl, phenyl-C ₁ -C ₄ -alkyl, and hetaryl-C ₁ -C ₄ -alkyl, where the ring in the last six radicals indicated may be unsubstituted or may carry 1, 2, 3, 4, or 5 substituents, which, each, independently of each other, selected from halogen, CN, NO ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, and C ₁ -C ₄ haloalkoxy;

R ^e , R ^f each, independently of each other, is selected from H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkylmethyl, C ₃ -C ₆ -halocycloalkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -haloalkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkylcarbonyl, C ₁ -C ₄ -haloalkylcarbonyl, C ₁ -C ₄ -alkylsulfonyl, C ₁ -C ₄ -haloalkylsulfonyl, heterocyclyl, heterocyclyl-C ₁ -C ₄ -alkyl, heterocyclylcarbonyl, heterocyclylsulfonyl, phenyl, phenylcarbonyl, phenylsulfonyl, hetaryl, hetarylcarbonyl, hetarylsulfonyl, phenyl-C ₁ -C ₄ -alkyl, and hetaryl-C ₁ -C ₄ -alkyl, where the ring in the last twelve indicated radicals may be unsubstituted or may carry 1, 2, 3, 4, or 5 substituents independently selected from halogen, CN, NO ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, and C ₁ -C ₄ haloalkoxy ; or

R ^e and R ^f together with the nitrogen atom to which they are bonded form a 5- to 6-membered, saturated or unsaturated heterocycle which may carry an additional heteroatom selected from O, S and N as the ring atom and where the heterocycle may be unsubstituted or may carry 1, 2, 3, 4, or 5 substituents each independently selected from halogen, CN, NO ₂ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ - haloalkyl, C ₁ -C ₄ -alkoxy, and C ₁ -C ₄ -haloalkoxy;

R ^g , R ^h each, independently of each other, is selected from H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -halocycloalkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -haloalkenyl, C ₂ -C ₄ -alkynyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, heterocyclyl, heterocyclyl-C ₁ -C ₄ -alkyl, phenyl, hetaryl, phenyl-C ₁ -C ₄ -alkyl, and hetaryl-C ₁ -C ₄ -alkyl, where the ring in the last six radicals indicated may be unsubstituted or may carry 1, 2, 3, 4, or 5 substituents, which are each independently selected from halogen, CN, NO ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, and C ₁ -C ₄ haloalkoxy ;

R ⁱ is selected from H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkylmethyl, C ₃ -C ₆ -halocycloalkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -haloalkenyl, C ₂ -C ₄ -alkynyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, phenyl, and phenyl-C ₁ -C ₄ -alkyl, where the phenyl ring in the last two radicals indicated may be unsubstituted or may carry 1, 2, 3, 4, or 5 substituents, each independently selected from halogen, CN, NO ₂ , C ₁ -C ₄ -alkyl , C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy, and C ₁ -C ₄ -haloalkoxy;

R ^x is selected from CN, NO ₂ , C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, S(O) _m R ^d , S(O) _m NR ^e R ^f , C ₁ -C ₁₀ -alkylcarbonyl , C ₁ -C ₄ -haloalkylcarbonyl, C ₁ -C ₄ -alkoxycarbonyl, C ₁ -C ₄ -haloalkoxycarbonyl, C ₃ -C ₆ -cycloalkyl, 5 - 7-membered heterocyclyl, 5 - 6 membered hetaryl, phenyl, C ₃ -C ₆ -cycloalkoxy, 3-6 membered heterocyclyloxy, and phenoxy, where the last 7 of these radicals may be unsubstituted or may carry 1, 2, 3, 4, or 5 radicals R ^y ;

R ^y is selected from halogen, CN, NO ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, S(O) _m R ^d , S(O) _m NR ^e R ^f , С ₁ -С ₄ -alkylcarbonyl, С ₁ -С ₄ -haloalkylcarbonyl, С ₁ -С ₄ -alkoxycarbonyl, С ₁ -С ₄ -haloalkoxycarbonyl, С ₃ -С ₆ -cycloalkyl , C ₃ -C ₆ halocycloalkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ haloalkenyl, C ₂ -C ₄ alkynyl, and C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl;

and where

Y is O or S; and

m is 0, 1 or 2;

and where

X ¹ is a leaving group which is preferably selected from halogen, N ₃ , p-nitrophenoxy, and pentafluorophenoxy.

In the preferred embodiment,

R ¹ is CH ₂ CH ₃ ;

R ² is C ₁ -C ₄ -alkyl, which may be unsubstituted,

or may be partially or fully halogenated;

R ³ is H;

and

R ^N is a -CR ⁴ R ⁵ R ⁶ group

where

R ⁴ is selected from C ₁ -C ₄ -alkyl, which may be unsubstituted, may be partially or completely halogenated, or may bear 1 or 2 identical or different R ^x substituents, where R ^x is selected from CN and C(O)NH ₂ , and

C ₃ -C ₆ -cycloalkyl, which may be unsubstituted or may carry 1, 2, or 3 identical or different substituents R ^y , where R ^y is selected from halogen, CN and C(O)NH ₂ ; and

R ⁵ is selected from C ₁ -C ₄ -alkyl, which may be unsubstituted, may be partially or completely halogenated, or may bear 1 or 2 identical or different R ^x substituents, where R ^x is selected from CN and C(O)NH ₂ , and

C ₃ -C ₆ -cycloalkyl, which may be unsubstituted or may carry 1, 2 or 3 identical or different substituents R ^y , where R ^y is selected from halogen, CN and C(O)NH ₂ ;

or

R ⁴ and R ⁵ together with the carbon atom to which they are attached form a 3- to 12-membered non-aromatic, saturated carbocycle, which may be partially or completely substituted with R ^j , where R ^j is selected from halogen, CN, and C (O)NH ₂ ; and

R ⁶ is H;

and

X ¹ is a leaving group which is preferably selected from halogen, N ₃ , p-nitrophenoxy, and pentafluorophenoxy, and particularly preferably is chlorine.

In a more preferred embodiment of the invention, R ^N is -CR ⁴ R ⁵ R ⁶ , and

R ¹ is CH ₂ CH ₃ ; and

R ² is CH ₃ , R ³ is H, R ⁴ is CH ₃ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ is CF ₃ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ is CH(CH ₃ ) ₂ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ is CHFCH ₃ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ is I-CN-cC ₃ H ₄ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ is 1-C(O)NH ₂ -cC ₃ H ₄ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ and R ⁵ together are CH ₂ CH ₂ CF ₂ CH ₂ CH ₂ , and R ⁶ is H; and

X ¹ is a leaving group which is preferably selected from halogen, N ₃ , p-nitrophenoxy, and pentafluorophenoxy, and is particularly preferably chlorine.

With regard to the reaction conditions for step (V), reference may be made to WO 2009/027393 and WO 2010/034737.

In the following, preferred embodiments relating to method B according to the invention are presented. It is understood that the preferred embodiments indicated above and those to be illustrated below for method B according to the invention are preferred alone or in combination with each other.

As already indicated above, the present invention relates to a second aspect of process B for the preparation of (a) a dichloropyridazinamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazinamine compound of formula IVb or a salt, tautomer or N-oxide thereof, or (c) mixtures of (a) and (b)

by reaction in one vessel, including the steps

interaction of a compound of formula II

with POCl ₃ , and

reaction of the resulting crude reaction product with an amino compound R ¹ -NH ₂ or a salt thereof,

where R ¹ represents H, C ₁ -C ₂ -alkyl, or C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl.

The reaction step underlying method B corresponds to steps (II)+(III) in the above reaction sequence.

As indicated above, the one-pot reaction is favorable because the intermediate trichloropyridazine compound of formula III, which is irritant, does not need to be isolated.

As already indicated above, it is understood that the compound of formula II may also be present in the form of its pyridazone tautomer.

It is understood that (a) or (b) or a mixture of (a) and (b) can be obtained in steps (II)+(III).

In a preferred embodiment, a mixture of (a) and (b) is obtained.

The substituent R ¹ in the compounds of formulas IVa and IVb, and the amine compound R ¹ -NH ₂ are preferably selected from the group consisting of CH ₃ , CH ₂ CH ₃ , and CH ₂ OCH ₃ .

In a preferred embodiment, R ¹ in the compounds of formulas IVa and IVb, and the amine compound R ¹ -NH ₂ is CH ₂ CH ₃ .

In a particularly preferred embodiment, a mixture of (a) and (b) is obtained, and R ¹ in the compounds of formulas IVa and IVb, and the amine compound R ¹ -NH ₂ is selected from the group consisting of CH ₃ , CH ₂ CH ₃ , and CH ₂ OCH ₃ , and preferably is CH ₂ CH ₃ .

The reaction conditions for steps (II) and (III), which are carried out sequentially in a single vessel reaction as defined above, without isolating the intermediate compound of formula III, have already been described above.

In a preferred embodiment of method B, the method further comprises step (I), i.e. the step of obtaining a compound of formula II

by the reaction of mucochloric acid (I)

with hydrazine or its salt.

The reaction conditions for this reaction step (I) have already been described above.

In another preferred embodiment of method B, the method further comprises step (IV), i.e. the step of converting (a) a dichloropyridazinamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazinamine compound of formula IVb or a salt thereof, tautomer or an N-oxide, or (c) a mixture of (a) and (b) to a pyridazinamine compound of formula V or a salt, tautomer or N-oxide thereof

by reacting (a) a dichloropyridazinamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazinamine compound of formula IVb or a salt, tautomer or N-oxide thereof, or (c) a mixture of (a) and (b)

with hydrogen in the presence of a hydrogenation catalyst,

where R ¹ is as defined above;

and where the method optionally further comprises step (V), i.e. the step of converting a pyridazinamine compound of formula V, or a salt, tautomer, or N-oxide thereof, to a compound of formula VII, or a stereoisomer, salt, tautomer, or N-oxide thereof

by reaction of a pyridazinamine compound of formula V or a salt, tautomer or N-oxide thereof

with a compound of formula VI or its stereoisomer, salt, tautomer or N-oxide

where R ¹ has the meaning as defined above, and

where R ² , R ³ , R ^N , and X ¹ have the meanings as defined above.

Preferred embodiments and reaction conditions for reaction steps (IV) and (V) have already been described above in connection with method A.

In the following, preferred embodiments relating to method C according to the invention are presented. It is understood that the preferred embodiments indicated above and those to be illustrated below for method C according to the invention are preferred alone or in combination with each other.

As already indicated above, the present invention relates in a third aspect to process C for the preparation of (a) a dichloropyridazinamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazinamine compound of formula IVb or a salt, tautomer or N-oxide thereof, or (c) mixtures of (a) and (b)

which includes the step of reacting a trichloropyridazine compound of formula III

with an amino compound R ¹ -NH ₂ or a salt thereof,

where R ¹ is CH ₂ CH ₃ ,

and wherein the method optionally further comprises the step of preparing a trichloropyridazine compound of formula III

by reacting a compound of formula II

with POCl ₃ .

The reaction step underlying Method C encompasses step (III) in the above reaction sequence, and optionally further step (II) as a separate step.

Surprisingly, it has been found that extremely high yields can be obtained in the reaction step (III) if ethylamine is used as the amine compound R ¹ -NH ₂ . In addition, labor-intensive processing is not necessary.

As already indicated above, it is understood that the compound of formula II may also be present in the form of its pyridazone tautomer.

It is understood that (a) or (b) or a mixture of (a) and (b) can be obtained in step (III).

In a preferred embodiment, a mixture of (a) and (b) is obtained.

The reaction conditions for steps (II) and (III), which are carried out separately according to method C, have already been described above.

In a preferred embodiment of method C, the method further comprises step (I), i.e. the step of obtaining a compound of formula II

by the reaction of mucochloric acid (I)

with hydrazine or its salt.

The reaction conditions for this reaction step (I) have already been described above.

In another preferred embodiment of Process C, the process further comprises step (IV), i.e. the step of converting (a) a dichloropyridazinamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazinamine compound of formula IVb or a salt thereof, tautomer or an N-oxide, or (c) a mixture of (a) and (b) to a pyridazinamine compound of formula V or a salt, tautomer or N-oxide thereof

by reacting (a) a dichloropyridazinamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazinamine compound of formula IVb or a salt, tautomer or N-oxide thereof, or (c) a mixture of (a) and (b)

with hydrogen in the presence of a hydrogenation catalyst,

where R ¹ is as defined above;

and where the method optionally further comprises step (V), i.e. the step of converting a pyridazinamine compound of formula V, or a salt, tautomer, or N-oxide thereof, to a compound of formula VII, or a stereoisomer, salt, tautomer, or N-oxide thereof

by reaction of a pyridazinamine compound of formula V or a salt, tautomer or N-oxide thereof

with a compound of formula VI or its stereoisomer, salt, tautomer or N-oxide

where R ¹ has the meaning as defined above, and

where R ² , R ³ , R ^N , and X ¹ have the meanings as defined above.

Preferred embodiments and reaction conditions for reaction steps (IV) and (V) have already been described above in connection with method A.

In the following, preferred embodiments relating to method D according to the invention are presented. It is understood that the preferred embodiments indicated above and those to be illustrated below for method D according to the invention are preferred alone or in combination with each other.

As already indicated above, the present invention relates in a further aspect to process D for the preparation of a compound of formula VII* or its stereoisomer, salt, tautomer or N-oxide

which includes the step of reacting a pyridazinamine compound of formula V or a salt, tautomer or N-oxide thereof

with a compound of formula VI* or its stereoisomer, salt, tautomer or N-oxide

where

R ¹ is CH ₂ CH ₃ ; and where

R ² is CH ₃ , R ³ is H, R ⁴ is CH ₃ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ is CF ₃ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ is CH(CH ₃ ) ₂ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ is CHFCH ₃ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ is I-CN-cC ₃ H ₄ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ is 1-C(O)NH ₂ -cC ₃ H ₄ , R ⁵ is CH ₃ and R ⁶ is H; or

R ² is CH ₃ , R ³ is H, R ⁴ and R ⁵ together are CH ₂ CH ₂ CF ₂ CH ₂ CH ₂ , and R ⁶ is H;

and where

X ¹ is a leaving group which is preferably selected from halogen, N ₃ , p-nitrophenoxy, and pentafluorophenoxy, and is particularly preferably chlorine.

The reaction step underlying process D is covered by step (V) of the reaction sequence described above.

In a preferred embodiment, the method further comprises step (IV) of the reaction sequence.

In a more preferred embodiment of the invention, the method further comprises step (III) and optionally also step (II), where steps (II) and (III) can be carried out separately by isolating a compound of formula III, or together in a single vessel reaction.

In an even more preferred embodiment, the method further comprises step (I).

Further details for steps (I), (II), (III), and (IV) have already been described above.

As already mentioned above, the present invention relates in another aspect to dichloropyridazinamine compound of formula IVa or its salt, tautomer or N-oxide;

where R ¹ represents CH ₂ CH ₃ ;

or a dichloropyridazinamine compound of formula IVb or a salt, tautomer or N-oxide thereof,

where R ¹ represents CH ₂ CH ₃ .

In a further aspect, the present invention relates to a mixture of a dichloropyridazinamine compound of formula IVa, or a salt, tautomer, or N-oxide thereof, and a dichloropyridazinamine compound of formula IVb, or a salt, tautomer, or N-oxide thereof, as defined above, i.e. wherein R ¹ is in each case CH ₂ CH ₃ .

These compounds are valuable starting materials for the preparation of 4-ethylaminopyridazine, which itself, for example, can be converted into the pesticidally active 4-pyrazole-N-pyridazinamide compounds of formula VII.

Typically, a mixture of a dichloropyridazinamine compound of formula IVa or a salt, tautomer or N-oxide thereof and a dichloropyridazinamine compound of formula IVb or a salt, tautomer or N-oxide thereof, as defined above, i.e. where R ¹ is in each case CH ₂ CH ₃ , can be obtained using methods B or C, as described in this application. Mixtures can be resolved into the components of (a) the dichloropyridazinamine compound of formula IVa, or a salt, tautomer, or N-oxide thereof, as well as (b) the dichloropyridazinamine compound of formula IVb, or a salt, tautomer, or N-oxide thereof, using separation techniques known to those skilled in the art. field of technology, for example, by column chromatography. However, separation of the two components is not required to obtain the pyridazinamine compound of formula V, since both components are suitable starting materials for the dehalogenation/hydrogenation reaction.

In a mixture, the components of (a) the dichloropyridazinamine compound of formula IVa or its salt, tautomer or N-oxide as well as (b) the dichloropyridazinamine compound of formula IVb or its salt, tautomer or N-oxide may be present in any ratio, preferably in a weight ratio in the range 100:1 to 1:100, preferably 10:1 to 1:10, more preferably 5:1 to 1:5, most preferably 2:1 to 1:2, particularly preferably 1:1.

Examples

I. Feature

Characterized by combined high performance liquid chromatography/mass spectrometry (HPLC/MS), by NMR, or by their melting points.

HPLC: Agilent Extend 1.8 µm C18 4.6 x 100 mm; mobile phase: A: water + 0.1% H ₃ PO ₄ ; B: acetonitrile (MeCN)+0.1% H ₃ PO ₄ ; gradient: 5-95% A over 10 minutes; 0-10 minutes is 5:95 A:B then gradient from 10-10.1 minutes to 95:5 A:B flow: 1.2 ml/min over 10 minutes at 60°C.

¹ H-NMR: Signals were characterized by chemical shift (frequently, per million) relative to tetramethylsilane, by their multiplicity and their integral (the relative number of hydrogen atoms represented). The following abbreviations are used to characterize signal multiplicity: m = multiplet, q = quartet, t = triplet, d = doublet and s = singlet.

Abbreviations used are: h for hour(s), min for minute, (t) and room temperature for 20-25°C.

II. Receipt examples

1. Preparation of a mixture of 3,4-dichloro-5-ethylaminopyridazine and 3,5-dichloro-4-ethylaminopyridazine using a one-pot procedure using 4,5-dichloro-3-hydroxypyridazine as starting material:

200 g of 4,5-dichloro-3-hydroxypyridazine was placed in a reactor at 20° C. under N ₂ and POCl ₃ (930 g, 5 equiv) was added and the reaction mixture was heated to 100° C. The reaction mixture was further stirred for ~1 hour until complete conversion was achieved. Excess POCl ₃ was removed by distillation. The reaction mixture was dosed in 1200 g H ₂ O, controlling the temperature at 30°C. Butyl acetate (1200 g) was added and the biphasic mixture was stirred for 30 minutes at 30° C. and then the phases were separated. Another portion of butyl acetate (400 g) was used to wash the aqueous phase. The combined organic phases were washed with 10% HCl and then H ₂ O.

To a mixture of trichloropyridazine in butyl acetate was added a solution of ethylamine in water at a concentration of 70 wt.% ethylamine based on the total weight of the solution (234 g, 3 equiv) at 35°C. The reaction was kept at 45°C for 3 hours (or until complete conversion). The phases were separated at 40° C. and the organic phase was washed once with H ₂ O. The combined aqueous phases were extracted once with butyl acetate. Butyl acetate from the combined organic phases was distilled off (15 mbar, 35° C.) to concentrate the reaction mixture. During this process, the product precipitated out of solution. The reaction mixture was cooled to 10°C and the product was filtered off. The mother liquor was then concentrated and the crude material was recrystallized from MTBE to isolate the remaining product.

2. Obtaining 4-ethylaminopyridazine:

600 g (3.09 mol) of a mixture of 3,4-dichloro-5-ethylaminopyridazine and 3,5-dichloro-4-ethylaminopyridazine was dissolved in EtOH (3.5 liters). 15 g (0.01 mol) 10% Pd/C was added and the pressurized reactor was purged with nitrogen. The high pressure reactor was pressurized to 0.2 bar with H ₂ and heated to 35°C. Since the reaction is exothermic, the temperature was controlled at 55° C. for 4 hours. After that, the pressure was reduced and the reactor was purged with N ₂ . The reaction mixture was filtered at room temperature to remove the catalyst. The catalyst can be reused in the next batch without purification.

In the second reactor, a mixture of K ₂ CO ₃ (1 kg) and 1 liter of EtOH was prepared. The reaction mixture was dosed into a solution of potassium carbonate for 60 minutes and the temperature was controlled at 20-25°C. The reaction mixture was further stirred for 3 hours. The salts obtained in the process were filtered off. A portion of the solvent from the reaction mixture was distilled off and MTBE was added to precipitate pure ethylaminopyridazine (354 g, 91% purity, 85% yield).

Claims (106)

1. Process for preparing a pyridazinamine compound of formula V or a salt or tautomer thereof

which comprises the step of reacting (a) a dichloropyridazinamine compound of formula IVa or a salt or tautomer thereof, or (b) a dichloropyridazinamine compound of formula IVb or a salt or tautomer thereof, or (c) a mixture of (a) and (b)

with hydrogen in the presence of a hydrogenation catalyst, where R ¹ is CH ₂ CH ₃ , wherein the method further comprises the step of preparing (a) a dichloropyridazinamine compound of formula IVa or a salt or tautomer thereof, or (b) a dichloropyridazinamine compound of formula IVb or a salt or tautomer thereof, or (c) a mixture of (a) and (b)

by reacting a trichloropyridazine compound of formula III

with an amino compound R ¹ -NH ₂ or a salt thereof, where R ¹ is CH ₂ CH ₃ , and wherein the method optionally further comprises the step of preparing a trichloropyridazine compound of formula III

by reacting a compound of formula II

with POCl ₃ . 2. The method according to p. 1, where the reaction is carried out in the absence of HCl neutralizer. 3. The process according to claim 1 or 2, wherein the HCl neutralizer is added after removal of the hydrogenation catalyst, wherein the HCl neutralizer is preferably provided without water. 4. The method according to any one of paragraphs. 1-3 wherein the HCl neutralizer is selected from the group consisting of bases including alkali metal and alkaline earth metal hydroxides, alkali metal and alkaline earth metal oxides, alkali metal and alkaline earth metal hydrides, alkali metal amides, alkali metal carbonates and alkaline earth metals, alkali bicarbonates, alkali metal alkyls, alkylmagnesium halides, alkali metal and alkaline earth metal alcoholates, nitrogen-containing bases including tertiary amines, pyridines, bicyclic amines, ammonia, and primary amines; and their combinations; buffers including sodium acetate and/or ammonium formate; ionic liquid precursors, including imidazoles; and their combinations. 5. The method according to any one of paragraphs. 1 to 4, wherein the hydrogenation catalyst is selected from the group consisting of supported platinum or palladium, Raney nickel, and Raney cobalt, and is preferably platinum or palladium on carbon. 6. The method according to any one of paragraphs. 1-5, where the method further comprises the step of obtaining a compound of formula II

by the reaction of mucochloric acid (I)

with hydrazine or its salt. 7. A method comprising the step of converting a pyridazinamine compound of formula V obtained by a method according to any one of paragraphs. 1-6, or a salt or tautomer thereof to a compound of formula VII, or a stereoisomer, salt, or tautomer thereof

by reacting a pyridazinamine compound of formula V or a salt or tautomer thereof

with a compound of formula VI or its stereoisomer, salt, or tautomer

where R ¹ has the meanings specified in paragraph 1, and where R ² is H, halogen, CN, NO ₂ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl, or C ₂ -C ₁₀ -alkynyl, where at least 3 of the last indicated radicals may be unsubstituted, may be partially or fully halogenated or may bear 1, 2 or 3 identical or different substituents R ^x , or OR ^a , SR ^a , C(Y)R ^b , C(Y)OR ^c , S(O)R ^d , S(O) ₂ R ^d , NR ^e R ^f , C(Y)NR ^g R ^h , heterocyclyl , hetaryl, C ₃ -C ₁₀ -cycloalkyl, C ₃ -C ₁₀ -cycloalkenyl or phenyl, where the last five indicated radicals may be unsubstituted or may carry 1, 2, 3, 4 or 5 identical or different substituents selected from the radicals R ^y and R ^x ; R ³ is H, halogen, CN, NO ₂ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl, or C ₂ -C ₁₀ -alkynyl, where at least 3 of the last indicated radicals may be unsubstituted, may be partially or fully halogenated or may bear 1, 2 or 3 identical or different substituents R ^x , or OR ^a , SR ^a , C(Y)R ^b , C(Y)OR ^c , S(O)R ^d , S(O) ₂ R ^d , NR ^e R ^f , C(Y)NR ^g R ^h , heterocyclyl , hetaryl, C ₃ -C ₁₀ -cycloalkyl, C ₃ -C ₁₀ -cycloalkenyl or phenyl, where the last five indicated radicals may be unsubstituted or may carry 1, 2, 3, 4 or 5 identical or different substituents selected from the radicals R ^y and R ^x ; R ^N is H, CN, NO ₂ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl, or C ₂ -C ₁₀ -alkynyl, where the last three radicals indicated may be unsubstituted, may be partially or completely halogenated or may carry 1, 2 or 3 identical or different substituents R ^x , or OR ^a , SR ^a , C(Y)R ^b , C(Y)OR ^c , S(O)R ^d , S(O) ₂ R ^d , NR ^e R ^f , C(Y)NR ^g R ^h , S (O) _m NR ^e R ^f , C(Y)NR ⁱ NR ^e R ^f , C ₁ -C ₅ -alkylene-OR ^a , C ₁ -C ₅ -alkylene-CN, C ₁ -C ₅ -alkylene-C (Y)R ^b , C ₁ -C ₅ -alkylene-C(Y)OR ^c , C ₁ -C ₅ -alkylene-NR ^e R ^f , C ₁ -C ₅ -alkylene-C(Y)NR ^g R ^h , C ₁ -C ₅ -alkylene-S(O) _m R ^d , C ₁ -C ₅ -alkylene-S(O) _m NR ^e R ^f , C ₁ -C ₅ -alkylene-NR ⁱ NR ^e R ^f , heterocyclyl, hetaryl, C ₃ -C ₁₀ -cycloalkyl, C ₃ -C ₁₀ -cycloalkenyl, heterocyclyl-C ₁ -C ₅ -alkyl, hetaryl-C ₁ -C ₅ -alkyl, C ₃ -C ₁₀ -cycloalkyl-C ₁ -C ₅ -alkyl, C ₃ -C ₁₀ -cycloalkenyl-C ₁ -C ₅ -alkyl, phenyl-C ₁ -C ₅ -alkyl, or phenyl, where the rings of the last ten indicated radicals may be unsubstituted or may carry 1, 2 , 3, 4 or 5 identical or different substituents R ^y ; and where R ^a , R ^b , R ^c are each independently selected from H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkylmethyl , C ₃ -C ₆ -halocycloalkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -haloalkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, heterocyclyl , heterocyclyl-C ₁ -C ₄ -alkyl, phenyl, hetaryl, phenyl-C ₁ -C ₄ -alkyl, and hetaryl-C ₁ -C ₄ -alkyl, where the ring in the last six indicated radicals may be unsubstituted or may carry 1 , 2, 3, 4, or 5 substituents, which are independently selected from halogen, CN, NO ₂ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy , and C ₁ -C ₄ haloalkoxy; R ^d is selected from C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkylmethyl, C ₃ -C ₆ -halocycloalkyl, C ₂ -C ₄ - alkenyl, C ₂ -C ₄ -haloalkenyl, C ₂ -C ₄ -alkynyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, heterocyclyl, heterocyclyl-C ₁ -C ₄ -alkyl, phenyl, hetaryl, phenyl-C ₁ -C ₄ -alkyl, and hetaryl-C ₁ -C ₄ -alkyl, where the ring in the last six radicals indicated may be unsubstituted or may carry 1, 2, 3, 4, or 5 substituents, which, each, independently of each other, selected from halogen, CN, NO ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, and C ₁ -C ₄ haloalkoxy; R ^e , R ^f each, independently of each other, is selected from H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkylmethyl, C ₃ -C ₆ -halocycloalkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -haloalkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkylcarbonyl, C ₁ -C ₄ -haloalkylcarbonyl, C ₁ -C ₄ -alkylsulfonyl, C ₁ -C ₄ -haloalkylsulfonyl, heterocyclyl, heterocyclyl-C ₁ -C ₄ -alkyl, heterocyclylcarbonyl, heterocyclylsulfonyl, phenyl, phenylcarbonyl, phenylsulfonyl, hetaryl, hetarylcarbonyl, hetarylsulfonyl, phenyl-C ₁ -C ₄ -alkyl, and hetaryl-C ₁ -C ₄ -alkyl, where the ring in the last twelve indicated radicals may be unsubstituted or may carry 1, 2, 3, 4, or 5 substituents independently selected from halogen, CN, NO ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, and C ₁ -C ₄ haloalkoxy ; or R ^e and R ^f together with the nitrogen atom to which they are bonded form a 5- to 6-membered, saturated or unsaturated heterocycle which may carry an additional heteroatom selected from O, S and N as the ring atom and where the heterocycle may be unsubstituted or may carry 1, 2, 3, 4, or 5 substituents each independently selected from halogen, CN, NO ₂ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ - haloalkyl, C ₁ -C ₄ -alkoxy, and C ₁ -C ₄ -haloalkoxy; R ^g , R ^h each, independently of each other, is selected from H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -halocycloalkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -haloalkenyl, C ₂ -C ₄ -alkynyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, heterocyclyl, heterocyclyl-C ₁ -C ₄ -alkyl, phenyl, hetaryl, phenyl-C ₁ -C ₄ -alkyl, and hetaryl-C ₁ -C ₄ -alkyl, where the ring in the last six radicals indicated may be unsubstituted or may carry 1, 2, 3, 4, or 5 substituents, which are each independently selected from halogen, CN, NO ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, and C ₁ -C ₄ haloalkoxy ; R ⁱ is selected from H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkylmethyl, C ₃ -C ₆ -halocycloalkyl, C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -haloalkenyl, C ₂ -C ₄ -alkynyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, phenyl, and phenyl-C ₁ -C ₄ -alkyl, where the phenyl ring in the last two radicals indicated may be unsubstituted or may carry 1, 2, 3, 4, or 5 substituents, each independently selected from halogen, CN, NO ₂ , C ₁ -C ₄ -alkyl , C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy, and C ₁ -C ₄ -haloalkoxy; R ^x is selected from CN, NO ₂ , C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, S(O) _m R ^d , S(O) _m NR ^e R ^f , C ₁ -C ₁₀ -alkylcarbonyl , C ₁ -C ₄ -haloalkylcarbonyl, C ₁ -C ₄ -alkoxycarbonyl, C ₁ -C ₄ -haloalkoxycarbonyl, C ₃ -C ₆ -cycloalkyl, 5-7-membered heterocyclyl, 5-6 membered hetaryl, phenyl, C ₃ -C ₆ -cycloalkoxy, 3-6 membered heterocyclyloxy, and phenoxy, where the last 7 of these radicals may be unsubstituted or may carry 1, 2, 3, 4, or 5 radicals R ^y ; R ^y is selected from halogen, CN, NO ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, S(O) _m R ^d , S(O) _m NR ^e R ^f , С ₁ -С ₄ -alkylcarbonyl, С ₁ -С ₄ -haloalkylcarbonyl, С ₁ -С ₄ -alkoxycarbonyl, С ₁ -С ₄ -haloalkoxycarbonyl, С ₃ -С ₆ -cycloalkyl , C ₃ -C ₆ halocycloalkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ haloalkenyl, C ₂ -C ₄ alkynyl, and C ₁ -C ₄ alkoxy-C ₁ -C ₄ alkyl; and where Y is O or S; and m is 0, 1 or 2; and where X ¹ is a leaving group which is preferably selected from halogen, N ₃ , p-nitrophenoxy, and pentafluorophenoxy. 8. The method according to claim 7, where R ¹ is CH ₂ CH ₃ ; R ² represents C ₁ -C ₄ -alkyl, which may be unsubstituted, or may be partially or completely halogenated; R ³ is H; and where R ^N is a group -CR ⁴ R ⁵ R ⁶ where R ⁴ is selected from C ₁ -C ₄ -alkyl, which may be unsubstituted, may be partially or completely halogenated, or may bear 1 or 2 identical or different R ^x substituents, where R ^x is selected from CN and C(O)NH ₂ , and C ₃ -C ₆ -cycloalkyl, which may be unsubstituted or may carry 1, 2, or 3 identical or different substituents R ^y , where R ^y is selected from halogen, CN and C(O)NH ₂ ; and R ⁵ is selected from C ₁ -C ₄ -alkyl, which may be unsubstituted, may be partially or completely halogenated, or may bear 1 or 2 identical or different R ^x substituents, where R ^x is selected from CN and C(O)NH ₂ , and C ₃ -C ₆ -cycloalkyl, which may be unsubstituted or may carry 1, 2 or 3 identical or different substituents R ^y , where R ^y is selected from halogen, CN and C(O)NH ₂ ; or R ⁴ and R ⁵ together with the carbon atom to which they are attached form a 3- to 12-membered non-aromatic, saturated carbocycle, which may be partially or completely substituted with R ^j , where R ^j is selected from halogen, CN, and C (O)NH ₂ ; and R ⁶ is H; and where X ¹ is a leaving group which is preferably selected from halogen, N ₃ , p-nitrophenoxy, and pentafluorophenoxy, and is particularly preferably chlorine. 9. Process for preparing (a) a dichloropyridazinamine compound of formula IVa or a salt or tautomer thereof, or (b) a dichloropyridazinamine compound of formula IVb or a salt or tautomer thereof, or (c) a mixture of (a) and (b)

which includes the step of reacting a trichloropyridazine compound of formula III

with an amino compound R ¹ -NH ₂ or a salt thereof, where R ¹ is CH ₂ CH ₃ , and wherein the method optionally further comprises the step of preparing a trichloropyridazine compound of formula III

by reacting a compound of formula II

with POCl ₃ . 10. The method of claim 9, wherein the method further comprises the step of obtaining a compound of formula II

by the reaction of mucochloric acid (I)

with hydrazine or its salt. 11. A method comprising the step of converting (a) a dichloropyridazinamine compound of formula IVa or a salt or tautomer thereof, or (b) a dichloropyridazinamine compound of formula IVb or a salt or tautomer thereof, or (c) a mixture of (a) and (b) obtained method according to claim 9 or 10, to a pyridazinamine compound of formula V or a salt or tautomer thereof

by reacting (a) a dichloropyridazinamine compound of formula IVa, or a salt or tautomer thereof, or (b) a dichloropyridazinamine compound of formula IVb, or a salt or tautomer thereof, or (c) a mixture of (a) and (b)

with hydrogen in the presence of a hydrogenation catalyst, where R ¹ has the meanings specified in paragraph 9; and wherein the method further comprises the step of converting a pyridazinamine compound of formula V, or a salt or tautomer thereof, to a compound of formula VII, or a stereoisomer, salt, or tautomer thereof

by reacting a pyridazinamine compound of formula V, or a salt or tautomer thereof

with a compound of formula VI or its stereoisomer, salt, or tautomer

where R ¹ has the meanings specified in clause 9, and where R ² , R ³ , R ^N , and X ¹ have the meanings specified in paragraph 7 or 8. 12. Mixture of intermediate dichloropyridazinamine compound of formula IVa

, where R ¹ is CH ₂ CH ₃ , and a dichloropyridazinamine intermediate of formula IVb

, where R ¹ is CH ₂ CH ₃ , to obtain a pyridazinamine compound of formula V.