JP7161275B2 - Method for producing 4-amino-pyridazine - Google Patents

Description

The present invention provides the following reaction sequence:

に従って式Vのピリダジンアミン化合物を製造するための方法に関する。

to a process for preparing pyridazine amine compounds of formula V according to.

In the scheme above and below, step (i) represents the conversion of mucochloric acid I to the compound of formula II, step (ii) represents the conversion of the compound of formula II to the trichloropyridazine compound of formula III, and step (iii) represents the conversion of the trichloropyridazine compound of formula III to a mixture of dichloropyridazineamine compounds of formula IVa and IVb, and step (iv) represents the mixture of compounds of formula IVa and IVb to the pyridazine compound of formula V. represents the conversion of It is emphasized that steps (ii) and (iii) can also be accomplished by a one-pot reaction illustrated by referring to steps (ii)+(iii) in the scheme above.

The resulting pyridazine amine compound of formula V can be reacted with a compound of formula VI according to the following reaction scheme to provide a compound of formula VII.

In the following, this reaction step will be referred to as step (v).

Pyridazine amine compounds, especially pyridazine amine compounds having an amino group at the 4-position of the pyridazine moiety, are versatile intermediate compounds for the production of pyridazine-derived fine chemicals, such as compounds in the pharmaceutical and agrochemical fields. For example, pyridazine amine compounds have been the focus of research investigations for pharmaceuticals suitable for the treatment of, for example, Alzheimer's dementia, depression, hypotension and anxiety. Additionally, the pyridazine amine compounds are useful for the production of pesticides having a pyridazine moiety, such as the 4-pyrazole-N-pyridazinamide compounds, which are known to be particularly useful for combating invertebrate pests. (see WO 2009/027393, WO 2010/034737, WO 2010/034738 and WO 2010/112177).

For certain applications, pyridazine amine compounds that do not contain any further substituents other than amino substituents, particularly pyridazine amine compounds that are not further substituted by halogen substituents, such as chlorine, are desired. However, since the typical starting material for making these compounds by nucleophilic substitution reactions with amine compounds is 3,4,5-trichloropyridazine, chlorine substituents are often present in pyridazine amine compounds.

In view of the above, there is a need for effective dehalogenation methods by which dichloropyridazineamine compounds can be converted to pyridazineamine compounds. In particular, there is a need for methods that provide improved yields. Considering the subsequent conversion of the resulting pyridazine amine, it is further desirable to carry out the reaction without adding water.

It is known in the art that dehalogenation of certain dichloropyridazine amine compounds can be carried out by a hydrogenation/dehalogenation reaction in the presence of hydrogen and a hydrogenation catalyst. It has been proposed in the art to carry out this hydrogenation/dehalogenation of pyridazine amine compounds in the presence of a base. In this regard, WO 2011/038572, Journal of Heterocyclic Chemistry, 21(5), 1389-92, 1984, WO 2009/152325, US 4,728,355, WO 2011/124524, WO 2010/049841, WO 2013/142269, US 6,258,822 and WO 2001/007436. For example, WO 2011/038572 describes the reaction of 3,5-dichloro-4-pyridazinamine with 5,6 by reacting the mixture with hydrogen in the presence of a hydrogenation catalyst (Pd/C) and a base (sodium hydroxide). -Dehalogenation of a mixture of dichloro-4-pyridazinamines is disclosed.

The reason the base is added is to avoid catalyst poisoning due to HCl formation in the reaction. This is illustrated by a paper on Pd-catalyzed dehalogenation of aromatic halides in F. Chang et al., Bull. Korean Chem. Soc. 2011, 32(3), 1075. HCl produced from dechlorination tends to be absorbed on activated carbon, leading to progressive poisoning of Pd/C, and adding some base to remove HCl is effective. is disclosed. It is further disclosed that the conversion in the dechlorination reaction can be increased in the presence of base.

However, the addition of bases is disadvantageous, especially for industrially applicable processes. First, an additional chemical is required for the reaction, namely a base, which makes the process more complicated. Second, the presence of base makes catalyst recycling difficult. In particular, when the hydrogenation catalyst is filtered off after the reaction, the chloride salts resulting from the reaction of the base with HCl are additionally filtered off, so that the filter cake consists of catalyst and chloride salts (e.g. KCl and KHCO ₃ ) includes both. Further workup procedures are then required to isolate the catalyst again.

International Publication No. WO 2009/027393 International Publication No. WO 2010/034737 International Publication No. WO 2010/034738 International Publication No. WO 2010/112177 International Publication No. WO 2011/038572 International Publication No. WO 2009/152325 U.S. Patent Application Publication No. US 4,728,355 International Publication No. WO 2011/124524 International Publication No. WO 2010/049841 International Publication No. WO 2013/142269 US Patent No. US 6,258,822 International Publication No. WO 2001/007436

Journal of Heterocyclic Chemistry, 21(5), 1389-92, 1984

It is therefore an object of the present invention to provide a process for the dehalogenation of dichloropyridazineamine 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 a further chemical and which offers the advantage that the hydrogenation catalyst can be recycled without purification after the reaction. At the same time, it is of course desirable that the process gives high yields.

The above object is achieved by method A as described below and in independent claim 1 and claims directly or indirectly dependent thereon.

Therefore, in a first aspect, the present invention provides a pyridazineamine compound of formula V or a salt, tautomer or N-oxide thereof

を製造するための方法であって、
(a)式IVaのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(b)式IVbのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(c) (a)と(b)の混合物

A method for manufacturing a
(a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c ) a mixture of (a) and (b)

と水素とを水素化触媒の存在下で反応させるステップ
(式中、
R¹は、H、C₁～C₂-アルキル又はC₁～C₂-アルコキシ-C₁～C₂-アルキルである)
を含む、以下において方法Aと称される方法に関する。

and hydrogen in the presence of a hydrogenation catalyst
(In the formula,
R ¹ is H, C ₁ -C ₂ -alkyl or C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl)
hereinafter referred to as method A, comprising

It should be noted that the reaction step underlying method A corresponds to step (iv) in the reaction sequence described above.

Surprisingly, the dehalogenation of the dichloropyridazine amine compound can be carried out in the absence of an HCl scavenger, i.e. in the absence of a base or another chemical suitable for binding HCl, and that the desired product can still be obtained in high yield. The hydrogenation catalyst can simply be filtered off after the reaction and recycled without purification.

Furthermore, it has been found that an HCl scavenger can be advantageously used after removal of the hydrogenation catalyst so that the hydrogen chloride is not bound and released in gaseous form.

When the HCl scavenger is used after removal of the hydrogenation catalyst, it has been found advantageous if the HCl scavenger is provided without water as it facilitates workup.

Furthermore, it was surprisingly found by the inventors of the present invention that the yield of dehalogenation of dichloropyridazineamine compounds depends on the nature of the amino substituent. In this connection, it has surprisingly been found that the reaction can be advantageously carried out using dichloropyridazineamine compounds in which the amino group is an ethylamino group.

Moreover, dichloropyridazine amine compounds are versatile intermediate compounds for the production of fine chemicals derived from pyridazine, such as compounds in the pharmaceutical and agrochemical fields. In particular, chlorine substituents allow for further derivatization of the pyridazine moiety, eg, introduction of additional amino groups by nucleophilic substitution reactions. Thus, a wide variety of compounds are available from dichloropyridazine amine compounds, not only because the amine group can react with, for example, an activated carboxylic acid derivative, but because the chlorine substituent can be replaced by other substituents.

Therefore, there is also a need for effective methods for the preparation of dichloropyridazine amine compounds.

Furthermore, there is a need to provide dichloropyridazineamine compounds or mixtures thereof in which the amino group is an ethylamino group, as these compounds are of particular interest as intermediates in the production of pesticides and pharmaceuticals. .

Typically, dichloropyridazine amine compounds are prepared starting from 3,4,5-trichloropyridazine by nucleophilic substitution reaction with an amine compound.

For example, WO 2011/038572 describes the synthesis of 3,5-dichloro-4-pyridazinamine and 5,6-dichloro-4- by reacting 3,4,5-trichloropyridazine with ammonia gas for a reaction time of 4 days. The preparation of mixtures of pyridazinamines is described. The same reaction is also described in US 4,728,355, where the reaction is carried out in a closed tube at a temperature of 120-130°C for 5 days. According to Tsukasa Kurais et al. (Journal of Heterocyclic Chemistry, 1964, Vol. 1, pp. 42-47), the reaction is carried out at 125° C. for 5 hours.

The above reaction conditions for this reaction have already indicated that the art suggests that either long reaction times or elevated temperatures are required for nucleophilic substitution reactions, and these Both are disadvantageous to commercial processes.

Furthermore, the preparation of dichloropyridazine amine compounds by reacting 3,4,5-trichloropyridazine with ammonia and different amine compounds appears to involve additional problems.

WO 99/64402 discloses the reaction of 3,4,5-trichloropyridazine with 3-amino-1-propanol as nucleophile. Although the reaction is carried out in boiling ethanol, the yield is very low (only 47.7% of the crude product) and laborious work-up by crystallization is required to isolate the desired reaction product. be done.

WO 2012/098387 discloses the reaction of 3,4,5-trichloropyridazine with 2-methylaminoethanol as nucleophile. Secondary amines, which are more nucleophilic than primary amines, are used as nucleophiles, but the reactions are not quantitative and require laborious work-up by column chromatography.

Donna L. Romero et al. (Journal of Medicinal Chemistry, 1996, Vol. 39, No. 19, pp. 3769-3789) disclose the reaction of 3,4,5-trichloropyridazine with isopropylamine as a nucleophile. ing. According to the information provided in the article, the reaction should be carried out in refluxing toluene, ie at a temperature of about 110°C. Additionally, chromatography is required for purification.

Similarly, WO 96/18628 discloses the same reaction, where 3,4,5-trichloropyridazine and isopropylamine are refluxed in toluene for 3 hours. Column chromatography is then required to isolate the desired compound 4-isopropylamino-3,5-dichloropyridazine.

Therefore, the processes for the preparation of dichloropyridazineamines, as described in the prior art, are all disadvantageous in terms of reaction conditions, yields and/or workup requirements.

Furthermore, the irritating compound 3,4,5-trichloropyridazine has to be prepared and handled as a starting material, which is another disadvantage of the methods described in the art. Solid handling of 3,4,5-trichloropyridazine is particularly disadvantageous on a commercial scale.

It is therefore an object of the present invention to overcome the disadvantages in terms of reaction conditions, yields and/or work-up requirements that are apparent from the prior art, or the disadvantages associated with the use of pungent 3,4,5-trichloropyridazine as starting material. It is an object of the present invention to provide a method for producing a dichloropyridazineamine compound that overcomes the drawbacks.

In this context, it is of particular interest to provide a direct process that is suitable for scale-up and provides satisfactory yields, preferably greater than 90%.

The above object is achieved by method B as described below and in independent claim 12 and claims directly or indirectly dependent thereon.

Thus, in a second aspect, the present invention provides (a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt or tautomer thereof. Mutants or N-oxides or (c) mixtures of (a) and (b)

を、
式II

of,
Formula II

の化合物とPOCl₃とを反応させるステップ、及び
結果として得られる粗反応生成物とアミン化合物R¹-NH₂又はその塩とを反応させるステップ
(式中、R¹は、H、C₁～C₂-アルキル又はC₁～C₂-アルコキシ-C₁～C₂-アルキルである)
を含むワンポット反応で製造するための、以下において方法Bと称される方法に関する。

with POCl3 _, and reacting the resulting crude reaction product with the amine compound R1 ^- _NH2 or a salt thereof.
(wherein R ¹ is H, C ₁ -C ₂ -alkyl or C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl)
hereinafter referred to as Method B for the preparation in a one-pot reaction comprising

The one-pot reaction that forms the basis of method B corresponds to steps (ii)+(iii) in the above reaction sequence.

Surprisingly, it has been found that the process for preparing dichloropyridazine amine compounds does not necessarily start with 3,4,5-trichloropyridazine. Alternatively, 3,4,5-trichloropyridazine can be prepared in situ in a one-pot reaction using the compound of formula II as starting material. The in situ formed 3,4,5-trichloropyridazine is then reacted directly with an amine compound to give the desired dichloropyridazine amine compound.

This method is particularly advantageous for safety reasons, as it does not require isolation and handling of the irritating compound 3,4,5-trichloropyridazine. This makes the method more suitable for industrial applications. Furthermore, the method is more economical and suitable for scale-up.

In addition, very high yields of dichloropyridazine amine compounds can be obtained by the above process, where the reaction of the in situ formed 3,4,5-trichloropyridazine with the amine compounds does not require harsh reaction conditions. was found. Due to the high yield, laborious work-up can also be avoided.

The above object is also achieved by method C as described below and in independent claim 13 and claims directly or indirectly dependent thereon.

Therefore, in a third aspect, the present invention provides (a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt or tautomer thereof. Mutants or N-oxides or (c) mixtures of (a) and (b)

を製造するための、
式III

for manufacturing
Formula III

のトリクロロピリダジン化合物とアミン化合物R¹-NH₂又はその塩とを反応させるステップ(式中、R¹はCH₂CH₃である)
を含み、
場合により、式III

with an amine compound R1 ^- _NH2 or a salt thereof _, wherein ^R1 is _CH2CH3 .
including
Optionally, formula III

のトリクロロピリダジン化合物を、式II

of the trichloropyridazine compound of formula II

の化合物とPOCl₃とを反応させることによって製造するステップをさらに含む、
以下において方法Cと称される方法に関する。

by reacting a compound of with _POCl3 ,
It relates to the method referred to below as method C.

It should be noted that the reaction step underlying method C is encompassed by step (iii) in the above reaction sequence. Optionally, step (ii) of the above reaction sequence is also performed.

Surprisingly, it has been found that this method of preparing dichloropyridazineamine compounds is particularly advantageous if ethylamine is used as the nucleophile in the nucleophilic substitution reaction. Although the prior art suggests harsh reaction conditions or at least very long reaction times for nucleophilic substitution reactions, moderate reaction conditions, e.g. It has been found by the inventors of the present invention to be sufficient to provide the desired dichloropyridazineethylamine in high yields and without laborious work-up.

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

(式中、R¹はCH₂CH₃である)
或いは式IVbのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド

(wherein R ¹ is CH ₂ CH ₃ )
or a dichloropyridazineamine compound of formula IVb or a salt, tautomer or N-oxide thereof

(式中、R¹はCH₂CH₃である)
に関する。

(wherein R ¹ is CH ₂ CH ₃ )
Regarding.

Furthermore, the present invention provides a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof and a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof as defined above. Concerning mixtures of N-oxides.

As already indicated above, these compounds are highly versatile precursors for the production of chemicals such as compounds in the pharmaceutical and agrochemical fields. They can also be used to advantage in hydrogenation/dehalogenation processes as described herein.

In a fifth aspect, the present invention provides compounds of formula VII ^* or stereoisomers, salts, tautomers or N-oxides thereof

の製造のための方法であって、
式Vのピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド

A method for the manufacture of
Pyridazineamine compounds of formula V or salts, tautomers or N-oxides thereof

と式VI^*の化合物又はその立体異性体、塩、互変異性体若しくはN-オキシド

and a compound of formula VI ^* or a stereoisomer, salt, tautomer or N-oxide thereof

とを反応させるステップ
(式中、
R¹はCH₂CH₃であり、かつ、
R²はCH₃であり、R₃はHであり、R⁴はCH₃であり、R⁵はCH₃であり、R⁶はHである、又は
R²はCH₃であり、R₃はHであり、R⁴はCF₃であり、R⁵はCH₃であり、R⁶はHである、又は
R²はCH₃であり、R₃はHであり、R⁴はCH(CH₃)₂であり、R⁵はCH₃であり、R⁶はHである、又はR²はCH₃であり、R₃はHであり、R⁴はCHFCH₃であり、R⁵はCH₃であり、R⁶はHである、又は
R²はCH₃であり、R₃はHであり、R⁴は1-CN-cC₃H₄であり、R⁵はCH₃であり、R⁶はHである、又は
R²はCH₃であり、R₃はHであり、R⁴は1-C(O)NH₂-cC₃H₄であり、R⁵はCH₃であり、R⁶はHである、又は
R²はCH₃であり、R₃はHであり、R⁴及びR⁵は一緒にCH₂CH₂CF₂CH₂CH₂であり、R⁶はHであり、かつ、式中、
X¹は、好ましくはハロゲン、N₃、p-ニトロフェノキシ及びペンタフルオロフェノキシから選択される脱離基であり、特に好ましくは塩素である)
を含む方法に関する。

the step of reacting with
(In the formula,
^R1 is _{CH2CH3 ,} and
^R2 is _CH3 , R3 is H, ^R4 is _{CH3 ,} ^R5 is _CH3 and ^R6 is H, or
^R2 is _CH3 , R3 is H, ^R4 is _{CF3 ,} ^R5 is _CH3 and ^R6 is H, or
^R2 is _CH3 , R3 is H, ^R4 is CH ⁽ _CH3 ) ₂ , R5 is _CH3 , ^R6 is H _, or ^R2 is _CH3 , R3 is H, ^R4 is _{CHFCH3 ,} ^R5 is _CH3 and ^R6 is H, or
^R2 is _{CH3 ,} R3 is H, ^R4 is ₁ ^- CN ^- _cC3H4 , R5 is _CH3 and R6 is H, or
^R2 is _{CH3 ,} R3 is H, ^R4 is ^{1 -} C(O) _{NH2 - cC3H4} , R5 is _CH3 and R6 is H, or
^R2 is _{CH3 , R3} is ^H , ^R4 and _{R5 together are} ^{CH2CH2CF2CH2CH2} , _R6 is H, and
X ¹ is preferably a leaving group selected from halogen, N ₃ , p-nitrophenoxy and pentafluorophenoxy, particularly preferably chlorine)
about a method comprising

This method will be referred to as method D below. The underlying reaction step of Method D is encompassed by step (v) in the above reaction sequence.

The method is such that the pyridazineamine compounds obtainable by the hydrogenation/dehalogenation process as described herein are pesticides suitable for controlling, for example, invertebrate pests. It has been shown to be an important intermediate in the production of 4-pyrazole-N-pyridazinamide compounds.

It should be understood that Methods A, B, C and D as defined above can optionally further comprise additional reaction steps of the reaction sequences provided above.

For example, Method A can optionally further comprise step (iii) and optionally step (ii), wherein steps (ii) and (iii) are separately or in a one-pot reaction + can be performed together as (iii). In addition, method A can optionally further comprise step (i). Furthermore, it should be understood that method A can optionally further comprise step (v).

Method B can optionally further comprise step (i) and/or step (iv). Additionally, step (v) can optionally follow step (iv).

Method C can optionally further comprise step (i) and/or step (iv). Additionally, step (v) can optionally follow step (iv).

Method D can optionally further comprise one or more of the preceding steps (iv), (iii), (ii) or (i) as indicated in the reaction sequence above.

Preferably, the reaction steps of the reaction sequences shown above, which are encompassed by methods A, B, C or D, are carried out separately, i.e. with or without isolation of intermediate compounds. , can be implemented. In particular, certain subsequent steps are preferably carried out in a one-pot reaction, eg as in steps (ii)+(iii).

Furthermore, it is emphasized that the reaction steps can each be performed on a technical scale. Preferably, the reactants are converted equally well and only minor deviations in terms of yields are observed.

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

"compounds of the invention" or "compounds according to the invention", i.e. formulas I, II, III, IVa, IVb, V, VI and VII (and VI ^* and VII ^* ) as defined herein includes the compounds as such and, if it is possible to form derivatives thereof, salts, tautomers or N-oxides thereof, which may be particularly true for compounds VI and VII and compounds VI ^* and VII ^* If a center of chirality exists, it also includes its stereoisomer.

As used herein, the term "pyridazine amine compound" refers to compounds of Formula V, ie, pyridazine compounds having an amino group -NHR ¹ as a substituent at the 4-position of the pyridazine moiety. Accordingly, the pyridazine amine compounds according to the invention do not contain any further substituents on the pyridazine ring.

As used herein, the term "dichloropyridazine amine compound" refers to a compound of Formula IVa or IVb or a combination thereof, i.e., a pyridazine compound having an amino group -NHR as ^a substituent and two chlorine substituents. wherein substituents are present at those positions of the pyridazine moiety that can be derived from Formulas IVa and IVb.

As used herein, the term "trichloropyridazine amine compound" preferably refers to the compound of formula III, ie 3,4,5-trichloropyridazine.

Depending on the acidity or basicity and the reaction conditions, the compounds of the invention may exist in the form of salts. Such salts are typically formed by reacting the compound with an acid if the compound has a basic functional group such as an amine, or by reacting the compound with a base if the compound has an acidic functional group such as a carboxylic acid group. obtained by letting

Cations resulting from the base reacting with the compounds according to the invention are for example the alkali metal cation M _a ⁺ , the alkaline earth metal cation M _ea ²⁺ or the ammonium cation NR ₄ ⁺ , wherein the alkali metal is preferably sodium, potassium or lithium, the alkaline earth metal cation is preferably magnesium or calcium, the substituents R of the ammonium cation NR ₄ ⁺ are preferably H, C ₁ -C ₁₀ -alkyl, phenyl and phenyl-C ₁ independently selected from -C2 _- alkyl; Suitable cations are in particular ions of alkali metals, preferably lithium, sodium and potassium, ions of alkaline earth metals, preferably calcium, magnesium and barium, and ions of transition metals, preferably manganese, copper, zinc and iron. , and additionally ammonium (NH ⁴⁺ ), and 1 to 4 of the hydrogen atoms are 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, substituted ammonium substituted by phenyl or benzyl. Examples of substituted ammonium ions are methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trimethylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxyethylammonium, 2-(2-hydroxyethoxy)ethylammonium, Bis(2-hydroxyethyl)ammonium, benzyltrimethylammonium and benzyl-triethylammonium, also phosphonium ions, sulfonium ions, preferably tri(C ₁ -C ₄ -alkyl)sulfonium, and sulfoxonium ions, preferably tri(C ₁ ∼C ₄ -alkyl)sulfoxonium.

Anions resulting from acids with which the compounds of the invention are reacted are, for example, chloride, bromide, fluoride, hydrogen sulfate, sulfate, dihydrogen phosphate, hydrogen phosphate, phosphate, nitrate, hydrogen Carbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate and anions of C ₁ -C ₄ -alkanoic acids, preferably formate, acetate, propionate and butyrate .

Tautomers of the compounds of the present invention include keto-enol tautomers, imine-enamine tautomers and amide-imidic acid tautomers. The compounds of the invention include all possible tautomers.

The term "N-oxide" relates to forms of the compounds of the invention in which at least one nitrogen atom is present in oxidized form (as NO). N-oxides of compounds of the invention can only be obtained if the compound contains an oxidizable nitrogen atom. N-oxides can primarily be prepared by standard methods, eg those described in Journal of Organometallic Chemistry 1989, 370, 17-31. However, it is preferred according to the present invention that the compounds do not exist in the form of N-oxides. On the other hand, under certain reaction conditions, the at least intermediate formation of N-oxides cannot be avoided.

The term "stereoisomer" includes both optical isomers, such as enantiomers or diastereomers, which exist due to more than one center of chirality in a molecule, as well as geometric isomers (cis/trans isomers). Depending on the substitution pattern, the compounds of the invention can possess one or more centers of chirality, in which case they can exist as mixtures of enantiomers or diastereomers. The invention provides both the pure enantiomers or diastereomers and mixtures thereof. Suitable compounds of the invention also include all possible geometric stereoisomers (cis/trans isomers) and mixtures thereof.

The compounds of the invention may be in solid or liquid form or in gas form. If the compounds exist as solids, they may be amorphous or may have different macroscopic properties such as stability or exhibit different biological properties such as activity. can exist in different crystalline states (polymorphs). The present invention includes both amorphous and crystalline compounds, mixtures of different crystalline states, and amorphous or crystalline salts thereof.

The organic moieties mentioned in the above definitions of the variables are, like the term halogen, generic terms for individual listings of individual group members. The prefixes C _n -C _m indicate in each case the possible number of carbon atoms in the group.

The term "halogen" denotes in each case fluorine, bromine, chlorine or iodine, especially fluorine, chlorine or bromine.

The term "alkyl" as used herein and in the alkyl portion of alkylamino, alkylcarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl and alkoxyalkyl typically has 1 to 10 carbon atoms, many Each case denotes a straight-chain or branched alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferably 1 to 3 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-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 herein and in the haloalkyl portion of haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylthio, haloalkylsulfonyl, haloalkylsulfinyl, haloalkoxy and haloalkoxyalkyl typically has 1 to 10 represents in each case a straight-chain or branched alkyl group having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, wherein the hydrogen atoms of this group are , is partially or wholly replaced by a halogen atom. Preferred haloalkyl moieties are from C ₁ -C ₄ -haloalkyl, more preferably from C ₁ -C ₃ -haloalkyl or C ₁ -C ₂ -haloalkyl, especially C ₁ -C ₂ -fluoroalkyl such as fluoromethyl, difluoromethyl , trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and pentafluoroethyl, and the like.

The term "alkoxy," as used herein, usually has 1 to 10 carbon atoms, often 1 to 6 carbon atoms, preferably 1 to 6 carbon atoms, attached through an oxygen atom. A straight-chain or branched alkyl radical having 1 to 4 carbon atoms is indicated in each case. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy and tert.-butyloxy and the like.

The term "alkoxyalkyl," as used herein, refers to an alkyl containing usually 1 to 10, often 1 to 4, preferably 1 to 2 carbon atoms, wherein The 1 carbon atom in has an alkoxy group which normally contains 1 to 4, preferably 1 or 2 carbon atoms as defined above. Examples are _CH2OCH3 , _{CH2 - OC2H5} , _2- (methoxy)ethyl and 2-(ethoxy)ethyl.

The term "haloalkoxy" as used herein has 1 to 10 carbon atoms, often 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. A straight-chain or branched alkoxy group is indicated in each case, wherein the hydrogen atoms of this group are partially or wholly replaced by halogen atoms, in particular fluorine atoms. Preferred haloalkoxy moieties include C ₁ -C ₄ -haloalkoxy, especially 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-difluoro-ethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2 , 2-trichloroethoxy and pentafluoroethoxy.

The term "alkylsulfonyl" (alkyl-S(=O) ₂ -), as used herein, means from one to refers to a straight-chain or branched, saturated alkyl group having 10 carbon atoms, preferably 1 to 4 carbon atoms (=C ₁ -C ₄ -alkylsulfonyl), preferably 1 to 3 carbon atoms .

The term "haloalkylsulfonyl", as used herein, refers to alkylsulfonyl groups as described above in which hydrogen atoms are partially or fully replaced by fluorine, chlorine, bromine and/or iodine. point to the base.

The term "alkylcarbonyl" refers to an alkyl group, as defined above, attached to the rest of the molecule through a carbonyl group (C=O) carbon atom.

The term "haloalkylcarbonyl" refers to an alkylcarbonyl group, as described above, in which hydrogen atoms are partially or fully replaced by fluorine, chlorine, bromine and/or iodine.

The term "alkoxycarbonyl" refers to an alkylcarbonyl group, as defined above attached through an oxygen atom to the remainder of the molecule.

The term "haloalkoxycarbonyl" refers to an alkoxycarbonyl group, as described above, in which hydrogen atoms are partially or fully replaced by fluorine, chlorine, bromine and/or iodine.

The term "alkenyl" as used herein refers to monounsaturated hydrocarbon radicals usually having 2 to 10, often 2 to 6 and preferably 2 to 4 carbon atoms. , e.g. vinyl, allyl(2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, methallyl(2-methylprop-2-en-1-yl), 2-butene- 1-yl, 3-buten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1-yl and 2- Ethylprop-2-en-1-yl etc. are indicated in each case.

The term "haloalkenyl," as used herein, refers to alkenyl groups, as defined above, in which hydrogen atoms have been partially or wholly replaced with halogen atoms.

The term "alkynyl" as used herein refers to monounsaturated hydrocarbon radicals usually having 2 to 10, often 2 to 6 and 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 yl, 1-pentyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 1-methylbut-2-yn-1-yl and 1-ethylprop-2-yn-1-yl, etc. is shown in each case.

The term "haloalkynyl," as used herein, refers to an alkynyl group, as defined above, in which hydrogen atoms have been partially or wholly replaced with halogen atoms.

The term "cycloalkyl," as used herein and in the cycloalkyl portion of cycloalkoxy and cycloalkylthio, refers to a monocyclic aliphatic Cyclic radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are in each case indicated.

The term "halocycloalkyl" as used herein and in the halocycloalkyl portion of halocycloalkoxy and halocycloalkylthio typically has 3 to 10 C atoms or 3 to 6 C In each case a monocyclic alicyclic radical having atoms is indicated in which at least one of the hydrogen atoms, for example 1, 2, 3, 4 or 5, is represented by halogen, in particular fluorine or chlorine. has been replaced by Examples are 1- and 2-fluorocyclopropyl, 1,2-, 2,2- and 2,3-difluorocyclopropyl, 1,2,2-trifluorocyclopropyl, 2,2,3,3-tetra fluorocyclopropyl, 1- and 2-chlorocyclopropyl, 1,2-, 2,2- and 2,3-dichlorocyclopropyl, 1,2,2-trichlorocyclopropyl, 2,2,3,3-tetra chlorocyclopropyl, 1-,2- and 3-fluorocyclopentyl, 1,2-, 2,2-, 2,3-, 3,3-, 3,4-, 2,5-difluorocyclopentyl, 1-, 2- and 3-chlorocyclopentyl, and 1,2-, 2,2-, 2,3-, 3,3-, 3,4-, 2,5-dichlorocyclopentyl and the like.

The term "cycloalkoxy" refers to a cycloalkyl group, as defined above, attached through an oxygen atom to the remainder of the molecule.

The term "cycloalkylalkyl" refers to compounds attached to the rest of the molecule via an alkyl group such as a C1-C5 _- alkyl group or a C1 _{- C4 -} alkyl group, especially a methyl group (=cycloalkylmethyl). refers to a cycloalkyl group as defined above.

The term "cycloalkenyl", as used herein and in the cycloalkenyl portion of cycloalkenyloxy and cycloalkenylthio, usually has 3 to 10, such as 3 or 4, or 5 to 10 Monocyclic monounsaturated non-aromatic radicals having 1 carbon atom, preferably 3 to 8 carbon atoms are indicated in each case. Exemplary cycloalkenyl groups include cyclopropenyl, cycloheptenyl or cyclooctenyl.

The term "halocycloalkenyl" as used herein and in the halocycloalkenyl portion of halocycloalkenyloxy and halocycloalkenylthio generally has 3 to 10, such as 3 or 4, or A monocyclic, monounsaturated, non-aromatic radical having in each case 5 to 10 carbon atoms, preferably 3 to 8 carbon atoms, wherein at least one hydrogen atom, such as one , 2, 3, 4 or 5 are replaced by halogen, in particular by fluorine or chlorine. Examples are 3,3-difluorocyclopropen-1-yl and 3,3-dichlorocyclopropen-1-yl.

The term "cycloalkenylalkyl" is attached to the remainder of the molecule via an alkyl group such as a C1-C5 _- alkyl group or a C1 _{- C4 -} alkyl group, especially a methyl group (=cycloalkenylmethyl). refers to a cycloalkenyl group as defined above.

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

The term "heterocycle" or "heterocyclyl" generally includes a 3- to 12-membered, preferably 3- to 8-membered or 5- to 8-membered, more preferably 5- or 6-membered, especially 6-membered monocyclic Heterocyclic non-aromatic groups are included. Heterocyclic non-aromatic groups usually have 1, 2, 3, 4 or 5, preferably 1, 2 or 3 hetero ring members selected from N, O and S. atoms, where the S atom as a ring member can be present as S, SO or _SO2 . Examples of 5- or 6-membered heterocyclic groups include saturated or unsaturated non-aromatic heterocyclic rings such as oxiranyl, 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, piperazinyl, pyranyl, 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 the like. Examples for heterocyclic rings also containing one or two carbonyl groups as ring members are pyrrolidin-2-onyl, pyrrolidin-2,5-dionyl, imidazolidin-2-onyl, oxazolidin-2-onyl and thiazolidine. -2-Onyl, etc.

The term "hetaryl" includes monocyclic 5- or 6-membered heteroaromatic radicals containing 1, 2, 3 or 4 heteroatoms selected from N, O and S as ring members. is included. Examples of 5- or 6-membered heteroaromatic groups are 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, such as 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, such as 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, such as 1H-, 2H- or 3H-1,2, 3-triazol-4-yl, 2H-triazol-3-yl, 1H-, 2H- or 4H-1,2,4-triazolyl and tetrazolyl, ie 1H- or 2H-tetrazolyl. The term "hetaryl" also includes bicyclic 8- to 10-membered heteroaromatic groups containing 1, 2 or 3 heteroatoms selected from N, O and S as ring members. wherein the 5- or 6-membered heteroaromatic ring is fused to the phenyl ring or to the 5- or 6-membered heteroaromatic group. Examples of 5- or 6-membered heteroaromatic rings fused to a phenyl ring or to a 5- or 6-membered heteroaromatic group include benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl benzoxadiazolyl, benzothiadiazolyl, benzoxazinyl, tinolinyl, isoquinolinyl, purinyl, 1,8-naphthyridyl, pteridyl, pyrido[3,2-d]pyrimidyl or pyridoimidazolyl. These fused hetaryl groups may be attached to the remainder of the molecule via any ring atom of the 5- or 6-membered heteroaromatic ring or via a carbon atom of the fused phenyl moiety.

The term "aryl" includes monocyclic, bicyclic or tricyclic aromatic groups usually having 6 to 14, preferably 6, 10 or 14 carbon atoms. Exemplary 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 attached to the rest of the molecule through an oxygen atom.

The terms "heterocyclylsulfonyl", "hetarylsulfonyl" and "phenylsulfonyl" refer respectively to heterocyclyl, hetaryl and phenyl attached to the rest of the molecule through the sulfur atom of the sulfonyl group.

The terms "heterocyclylcarbonyl", "hetarylcarbonyl" and "phenylcarbonyl" refer respectively to heterocyclyl, hetaryl and phenyl attached to the remainder of the molecule through the carbon atom of a carbonyl group (C=O).

The terms “heterocyclylalkyl” and “hetarylalkyl” refer to the addition of a molecule via a C ₁ -C ₅ -alkyl group or a C ₁ -C ₄ -alkyl group, especially a methyl group (=heterocyclylmethyl or hetarylmethyl respectively). Refers to heterocyclyl or hetaryl, respectively, as defined above attached to the remainder.

The term “phenylalkyl” denotes a C ₁ -C ₅ -alkyl group or a C ₁ -C ₄ -alkyl group, in particular a phenyl which is attached to the rest of the molecule via a methyl group (=arylmethyl or phenylmethyl). Examples include benzyl, 1-phenylethyl, 2-phenylethyl, and the like.

The term "alkylene" refers to alkyl, as defined above, which represents a linker between the molecule and the substituent.

Preferred embodiments for methods A, B, C and D of the invention are described below.

Generally, the reaction steps carried out in Methods A, B, C and D, as described in detail below, are carried out in reaction vessels customary for such reactions, the reactions being carried out continuously, semi-continuously or batchwise. method.

Generally, the specific reactions are carried out under atmospheric pressure. The reaction can, however, also be carried out under reduced pressure.

The temperature and duration of the reaction may vary over a wide range known to those skilled in the art from analogous reactions. The temperature often depends on the reflux temperature of the solvent. Other reactions are preferably carried out at room temperature, ie about 25°C, or under ice cooling, ie about 0°C. Completion of the reaction can be monitored by methods known to those skilled in the art, such as thin layer chromatography or HPLC.

Unless otherwise indicated, the molar ratio of reactants used in the reaction is 0.2:1 to 1:0.2, preferably 0.5:1 to 1:0.5, more preferably 0.8:1 to 1:0.8. Range. Preferably, equimolar amounts are used.

Unless otherwise indicated, the reactants can in principle be contacted with each other in any desired order.

It is known to those skilled in the art that if the reactants or reagents are moisture sensitive, the reaction should be carried out under protective gas, eg under a nitrogen atmosphere, and dry solvents should be used.

The person skilled in the art also knows the best work-up of the reaction mixture after the reaction has ended.

In the following, preferred embodiments for method A of the invention are provided. It should be understood that the preferred embodiments of method A of the invention described above and those further exemplified below are to be understood as preferred either alone or in combination with each other. is.

As already indicated above, the present invention provides, in a first aspect, a pyridazineamine compound of formula V or a salt, tautomer or N-oxide thereof

を製造する方法Aであって、
(a)式IVaのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(b)式IVbのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(c) (a)と(b)の混合物

A method A for manufacturing a
(a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c ) a mixture of (a) and (b)

と水素とを水素化触媒の存在下で反応させるステップ
(式中、
R¹は、H、C₁～C₂-アルキル又はC₁～C₂-アルコキシ-C₁～C₂-アルキルである)
を含む方法に関する。

and hydrogen in the presence of a hydrogenation catalyst
(In the formula,
R ¹ is H, C ₁ -C ₂ -alkyl or C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl)
about a method comprising

The underlying reaction step of Method A corresponds to step (iv) in the above reaction sequence.

Reaction step (iv) can only be carried out in the presence of a hydrogenation catalyst.

As used herein, the term "hydrogenation catalyst" includes heterogeneous and homogeneous hydrogenation catalysts, but preferably refers to heterogeneous catalysts. Platinum, palladium, rhodium and ruthenium are known in the art to form highly active catalysts. Non-noble metal catalysts such as those based on nickel (such as Raney nickel and Urushibara nickel) are economical alternatives. Preferred hydrogenation catalysts according to the invention are further provided below.

Hydrogen chloride is produced as a by-product of reaction step (iv).

Nevertheless, in a preferred embodiment of Method A, the reaction is carried out in the absence of HCl scavenger. Surprisingly, it has been found that compounds of formula V are obtained in higher yields if no HCl scavenger is present in the reaction mixture.

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

Preferably, the term "HCl scavenger" as used herein is a chemical added to the reaction mixture, which comprises the starting material of the reaction, i.e. the compound of formula (IVa) or (IVb). should be understood to refer to chemical substances that do not contain

Therefore, reaction step (iv) is preferably carried out in the absence of any additionally provided chemical that functions as an HCl scavenger.

Reaction step (iv) is preferably carried out in the absence of an HCl scavenger, so that the HCl produced is still in the reaction mixture when the hydrogenation catalyst is removed.

Therefore, in another preferred embodiment of method A, the HCl scavenger is added after removal of the hydrogenation catalyst. Preferably, the HCl scavenger is provided without water. In order to avoid loss of the compound in the aqueous phase, allow for easier work-up, and avoid the need to dry the compound prior to further reaction, the reaction product, i. It has been found advantageous to retain.

The HCl scavenger, preferably added only after removal of the hydrogenation catalyst, can be selected primarily 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 Nitrogen-containing bases including metal bicarbonates, alkali metal alkyls, alkylmagnesium halides, alkali metal and alkaline earth metal alcoholates, and tertiary amines, pyridines, bicyclic amines, ammonia and primary amines. .

Buffers include aqueous and non-aqueous buffers, preferably non-aqueous buffers. Preferred buffers include acetate or formate based buffers such as sodium acetate or ammonium formate.

Precursors of ionic liquids include imidazole.

In a preferred embodiment of method A of the present invention, the HCl scavenger is alkali metal and alkaline earth metal hydroxides, alkali metal and alkaline earth metal oxides, alkali metal and alkaline earth metal hydrides, alkali metal amides, Bases including alkali metal and alkaline earth metal carbonates, alkali metal bicarbonates, alkali metal alkyls, alkylmagnesium halides, alkali metal and alkaline earth metal alcoholates, tertiary amines, pyridines, bicyclic amines, ammonia and nitrogen-containing bases, including primary amines, and combinations thereof; buffer solutions, including sodium acetate and/or ammonium formate; precursors of ionic liquids, including imidazole; and combinations thereof.

In one preferred embodiment, the HCl scavenger comprises at least one base.

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

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

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

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

In another particularly preferred embodiment, the base is selected from alkylmagnesium halides, 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 tert-butanolate and dimethoxymagnesium.

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

In another particularly preferred embodiment, the base is pyridine, including collidine, lutidine and substituted pyridines such as 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, especially ethylamine.

In a most preferred embodiment of method A of the present invention, the HCl scavenger is potassium hydroxide or any one of the carbonates defined above.

The base can be used in equimolar amounts, in excess, or as solvent if appropriate.

In another preferred embodiment, the HCl scavenger comprises at least one buffer.

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

In another preferred embodiment, the HCl scavenger comprises an ionic liquid precursor.

In a particularly preferred embodiment, the ionic liquid precursor is an imidazole compound that forms an ionic liquid after reacting with HCl released in a hydrogenation/dehalogenation reaction. The non-polar organic phase containing the desired pyridazine amine compound can then be conveniently separated from the newly formed ionic liquid.

As already indicated above, any hydrogenation catalyst known in the art, in particular a heterogeneous hydrogenation catalyst, can be used for reaction step (iv).

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 invention, the hydrogenation catalyst is selected from the group consisting of platinum or palladium on a support, Raney nickel and Raney cobalt, preferably platinum or palladium on carbon.

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

In a particularly preferred embodiment, the hydrogenation catalyst is palladium or platinum on carbon, wherein the content of palladium or platinum is preferably from 0.1% to 15% by weight, based on the support material, more preferably It ranges from 0.5% to 10% by weight.

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

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

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

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

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

(a) a dichloropyridazineamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of formula IVb or a salt, tautomer It is emphasized that either isomers or N-oxides or (c) mixtures of (a) and (b) can be used.

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

Substituent ^R1 in compounds of formulas IVa, _IVb and V is preferably selected from the group consisting of _{CH3 , CH2CH3} and _CH2OCH3 .

In preferred embodiments of Method A, R ¹ in 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 ^R1 in compounds of formulas IVa, IVb and V is the group consisting of _{CH3 , CH2CH3} and _CH2OCH3 . is _{preferably CH2CH3} .

Mild reaction conditions are preferred for reaction step (iv).

In a preferred embodiment, the hydrogen pressure applied is in the range 0.1 bar to 10 bar, preferably in the range 0.1 bar to 1 bar, more preferably in the range 0.1 bar to 0.5 bar. If the starting material contains impurities in amounts of more than 2% by weight or more than 5% by weight, higher pressures in the range from 0.6 bar to 10 bar, preferably from 1 bar to 5 bar may be advantageous.

In a preferred embodiment, the reaction temperature is kept in the range of 20°C to 100°C, preferably in the range of 20°C to 65°C. The reaction mixture is preferably heated to 30° C. to 40° C. after charging hydrogen to the pressure reactor in which the reaction is preferably carried out. However, as the hydrogenation reaction is exothermic, it may be necessary to keep the temperature below 60° C., preferably by cooling the reaction mixture afterwards. A reaction temperature in the range from 50°C to 60°C is particularly preferred.

Reaction times may vary over a wide range. Preferred reaction times are in the range 1 to 12 hours, preferably in the range 3 to 6 hours, eg 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 p-xylene; halogenated hydrocarbons such as methylene chloride; chloroform and chlorobenzene; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol; _C2 - _C4 -alkanediols such as ethylene glycol or propylene glycol; ether alkanols such as diethylene glycol; N-methylpyrrolidone; dimethylformamide; and ethers including open-chain and cyclic ethers, especially diethyl ether, methyl-tert-butyl-ether (MTBE), 2-methoxy-2-methylbutane, cyclopentyl methyl ether, 1,4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, especially tetrahydrofuran, MTBE and 2-methyltetrahydrofuran. Mixtures of said 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 tert-butanol.

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

As explained above, method A can include not only reaction step (iv), but also other reaction steps of the reaction sequences described above.

In particular, method A can optionally further comprise step (iii) and optionally step (ii), wherein steps (ii) and (iii) separately or step (ii) in a one-pot reaction + can be performed together as (iii). In addition, method A can optionally further comprise step (i). Furthermore, it should be understood that method A can optionally further comprise step (v).

In one embodiment of Method A, the method comprises reaction steps (ii)+(iii), i.e. (a) the dichloropyridazineamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) ) a dichloropyridazineamine compound of formula IVb or a salt, tautomer or N-oxide thereof, or (c) a mixture of (a) and (b)

を、
式II

of,
Formula II

の化合物とPOCl₃とを反応させるステップ、及び
結果として得られる粗反応生成物とアミン化合物R¹-NH₂又はその塩とを反応させるステップ
を含むワンポット反応で製造するステップ
(式中、R¹は、H、C₁～C₂-アルキル又はC₁～C₂-アルコキシ-C₁～C₂-アルキルである)
をさらに含む。

and POCl3 _, and reacting the resulting crude reaction product with the amine compound R1 ^- _NH2 or a salt thereof, in a one-pot reaction.
(wherein R ¹ is H, C ₁ -C ₂ -alkyl or C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl)
further includes

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

It should be 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 ^R1 in the compounds of _formula IVa and IVb and the amine compounds R1 ^- _NH2 is preferably selected from the group consisting of _{CH3 , CH2CH3} and _CH2OCH3 .

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

In a particularly preferred embodiment, a mixture of (a) and ₍ b) is obtained and R1 in the compounds of formulas IVa and IVb and the amine compound ^{R1 -} _NH2 is _{CH3 , CH2CH3} and _CH2OCH3 is selected from the group consisting of _, preferably _CH2CH3 .

It should be understood that the compounds of formula II may also exist in the form of their pyridazone tautomers.

The reaction conditions for subsequent steps (ii) and (iii) in a one-pot reaction as defined above without isolation of the intermediately obtained compound of formula III are further detailed below. defined in

In an alternative embodiment of Method A, the method comprises reacting step (iii), i.e. (a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) Dichloropyridazineamine compounds or salts, tautomers or N-oxides thereof, or (c) a mixture of (a) and (b)

を、
式III

of,
Formula III

のトリクロロピリダジン化合物とアミン化合物R¹-NH₂又はその塩とを反応させることによって製造するステップ
(式中、R¹は、H、C₁～C₂-アルキル又はC₁～C₂-アルコキシ-C₁～C₂-アルキルである)
をさらに含み、
該方法は、場合により、反応ステップ(ii)、即ち、式III

by reacting a trichloropyridazine compound with an amine compound R ¹ —NH ₂ or a salt thereof
(wherein R ¹ is H, C ₁ -C ₂ -alkyl or C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl)
further comprising
The method optionally comprises reaction step (ii), i.e. formula III

のトリクロロピリダジン化合物を、
式II

the trichloropyridazine compound of
Formula II

の化合物とPOCl₃とを反応させることによって製造するステップをさらに含む。

with _POCl3 .

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

It should be 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 substituent ^R1 in the compounds of _formula IVa and IVb and the amine compounds R1 ^- _NH2 is preferably selected from the group consisting of _{CH3 , CH2CH3} and _CH2OCH3 .

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

In a particularly preferred embodiment, a mixture of (a) and ₍ b) is obtained and R1 in the compounds of formula IVa and IVb and the amine compound ^{R1 -} _NH2 is _{CH3 , CH2CH3} and _CH2OCH3 is selected from the group consisting of _, preferably _CH2CH3 .

As already indicated above, it should be understood that the compounds of formula II may also exist in the form of their pyridazone tautomers.

The reaction conditions for steps (ii) and (iii), which also apply to situations carried out in a one-pot reaction as steps (ii)+(iii), are defined below.

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 compound of formula II.

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

In another particularly preferred embodiment POCl ₃ is present in an amount of more than 2.0 mol to 10 mol per mol of compound of formula II, preferably in an amount of 4.0 mol to 6.0 mol, especially from 4.8 mol to 1 mol of compound of formula II. Used in an amount of 5.2 mol.

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

Reaction step (ii) is preferably carried out in the absence of a solvent.

More preferably, the reaction is carried out in a protective gas atmosphere, eg under nitrogen.

The reaction temperature can range from 60°C to 130°C, preferably from 100°C to 125°C.

Reaction times may vary over a wide range, preferably in the range 1 to 24 hours, preferably in the range 1 to 5 hours, more preferably in the range 1 to 2 hours.

After reaction, excess POCl ₃ can be removed under reduced pressure. Water is then preferably added to the reaction mixture upon 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 connection include dichloromethane, iso-butanol, ethyl acetate and butyl acetate, especially butyl acetate.

For the preparation and isolation of trichloropyridazine compounds of formula III, 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 , 1997-2000.

The step of isolating the trichloropyridazine compound of formula III can be omitted if the one-pot reaction procedure is performed as defined above. 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 aqueous sodium hydroxide (eg, 10% aqueous NAOH) and/or water prior to 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 R1 ^- _NH2 is in gaseous form, it can be provided either as a solution or as a gas.

A particularly preferred amine compound is ethylamine, as already indicated 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-butanol, especially ethanol.

In one preferred embodiment, the solvent in which the amine compound R1 ^- _NH2 is provided is water. Suitable concentrations range from 10 wt.-% to 100 wt.-%, preferably 40 wt.-% to 90 wt.-%, more preferably 60% to 80%, most preferably 60% to 80%, based on the total weight of the solution. 66wt.-% to 72wt.-%.

In a particularly preferred embodiment, the amine compound R1 ^- _NH2 is ethylamine, as an aqueous solution, at a concentration ranging from 60% to 80%, preferably from 66 wt.-% to 72 wt.-%, based on the total weight of the solution. provided.

It is a surprising finding of the present invention that the presence of water in the reaction mixture does not negatively affect the yield of reaction step (iii).

In another preferred embodiment, the amine compound R ¹ —NH ₂ is provided in gaseous form and is introduced into the reaction mixture by bubbling it into the solvent, wherein reaction step (iii) is carried out, wherein The trichloropyridazine compound of III may already be dissolved. Preferred solvents in this context include protic solvents, preferably alcohols selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol. Ethanol is particularly preferred as solvent. Furthermore, preferred solvents in which the gaseous amine compound R1 ^- _NH2 may be dissolved by reaction step (iii) generally include toluene, THF and ethanol.

Preferably an excess of the amine compound R1 ^- _NH2 is used.

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

Suitable solvents for the reaction include water and aliphatic hydrocarbons such as pentane, hexane, cyclohexane and petroleum ether; aromatic hydrocarbons such as toluene, o-, m- and p-xylene; halogenated hydrocarbons. , such as methylene chloride, chloroform and chlorobenzene; alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol; _C2 - _C4 -alkanediols, such as ethylene glycol or propylene glycol; ether alkanols, such as diethylene glycol; carboxylic acid esters such as ethyl acetate; N-methylpyrrolidone; dimethylformamide; Cyclopentyl methyl ether, 1,4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, especially tetrahydrofuran, MTBE and 2-methyltetrahydrofuran. Mixtures of said 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, eg a mixture of water and butyl acetate.

Alternatively, the reaction is carried out in a protic solvent, preferably selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, especially if the amine compound is provided in gaseous form. It is particularly preferred to be carried out in an alcohol, especially ethanol. Reaction step (iii) is then carried out in this protic solvent, and reaction step (iv) is optionally followed directly in a one-pot reaction using excess amine compound as HCl scavenger. can be done.

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

In connection with the amine compound R1 ^- _NH2 as defined herein, especially the amine compound R1 ^- _NH2 being ethylamine, the following reaction temperatures are particularly preferred.

In one embodiment, reaction step (iii) is performed at a temperature of 100°C or less.

In another embodiment, reaction step (iii) is performed at a temperature of 80° C. or less.

In another embodiment, reaction step (iii) is performed at a temperature of 70°C or less.

In another embodiment, reaction step (iii) is performed at a temperature of 60°C or less.

In one embodiment, reaction step (iii) is performed at a temperature of 0°C to 100°C.

In another embodiment, reaction step (iii) is performed at a temperature of 0°C to 80°C.

In another embodiment, reaction step (iii) is performed at a temperature of 0°C to 70°C.

In another embodiment, reaction step (iii) is performed at a temperature of 0°C to 60°C.

In a preferred embodiment, reaction step (iii) is carried out at a temperature of 20°C to 80°C.

In another preferred embodiment, reaction step (iii) is carried out at a temperature of 20°C to 70°C.

In another preferred embodiment, reaction step (iii) is performed at a temperature of 20°C to 60°C.

In a particularly preferred embodiment, reaction step (iii) is carried out at a temperature of 25°C to 60°C.

Reaction times vary over a wide range, for example from 1 hour to 4 days. Preferably, the reaction time is in the range from 1 hour to 24 hours, especially from 1 hour to 12 hours. More preferably, the reaction time ranges from 1 hour to 5 hours, preferably from 3 hours to 4 hours.

Concerning reaction step (iii), reference is also made to US 4,728,355.

As already indicated above, method A can optionally further comprise step (i) to provide a compound of formula II.

In one embodiment of Method A, the method also includes step (i) in addition to steps (ii) and (iii) performed either separately or as a one-pot reaction, i.e., the method comprises formula II

の化合物を、
ムコクロル酸I

a compound of
Mucochloric acid I

とヒドラジン又はその塩とを反応させることによって製造するステップをさらに含む。

and hydrazine or a salt thereof.

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

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

Hydrazine is preferably provided in salt form, preferably as hydrazine sulfate.

Suitable solvents include protic solvents such as water.

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

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

As already indicated above, method A optionally further comprises step (v).

In one embodiment of Method A, the method further comprises step (v), i.e., the method comprises treating a pyridazineamine compound of Formula V or a salt, tautomer or N-oxide thereof with a compound of Formula VII or stereoisomers, salts, tautomers or N-oxides thereof

に、
式Vのピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド

to the
Pyridazineamine compounds of formula V or salts, tautomers or N-oxides thereof

と式VIの化合物又はその立体異性体、塩、互変異性体若しくはN-オキシド

and a compound of formula VI or a stereoisomer, salt, tautomer or N-oxide thereof

とを反応させることによって変換するステップ
(式中R¹は、H、C₁～C₂-アルキル又はC₁～C₂-アルコキシ-C₁～C₂-アルキルであり、
式中、
R²は、H、ハロゲン、CN、NO₂、C₁～C₁₀-アルキル、C₂～C₁₀-アルケニル又はC₂～C₁₀-アルキニルであり、最後に挙げた3個の基は、非置換であってもよく、部分的若しくは完全にハロゲン化されていてもよく、又は1個、2個若しくは3個の同一若しくは異なる置換基R^xを有していてもよく、或いは
OR^a、SR^a、C(Y)R^b、C(Y)OR^c、S(O)R^d、S(O)₂R^d、NR^eR^f、C(Y)NR^gR^h、ヘテロシクリル、ヘタリール、C₃～C₁₀-シクロアルキル、C₃～C₁₀-シクロアルケニル又はフェニルであり、最後に挙げた5個の基は、非置換であってもよく、又はR^y及びR^x基から選択される1個、2個、3個、4個若しくは5個の同一若しくは異なる置換基を有していてもよく、
R³は、H、ハロゲン、CN、NO₂、C₁～C₁₀-アルキル、C₂～C₁₀-アルケニル又はC₂～C₁₀-アルキニルであり、最後に挙げた3個の基は、非置換であってもよく、部分的若しくは完全にハロゲン化されていてもよく、又は1個、2個若しくは3個の同一若しくは異なる置換基R^xを有していてもよく、或いは
OR^a、SR^a、C(Y)R^b、C(Y)OR^c、S(O)R^d、S(O)₂R^d、NR^eR^f、C(Y)NR^gR^h、ヘテロシクリル、ヘタリール、C₃～C₁₀-シクロアルキル、C₃～C₁₀-シクロアルケニル又はフェニルであり、最後に挙げた5個の基は、非置換であってもよく、又はR^y及びR^x基から選択される1個、2個、3個、4個若しくは5個の同一若しくは異なる置換基を有していてもよく、
R^Nは、H、CN、NO₂、C₁～C₁₀-アルキル、C₂～C₁₀-アルケニル又はC₂～C₁₀-アルキニルであり、最後に挙げた3個の記述されている基は、非置換であってもよく、部分的若しくは完全にハロゲン化されていてもよく、又は1個、2個若しくは3個の同一若しくは異なる置換基R^xを有していてもよく、或いはOR^a、SR^a、C(Y)R^b、C(Y)OR^c、S(O)R^d、S(O)₂R^d、NR^eR^f、C(Y)NR^gR^h、S(O)_mNR^eR^f、C(Y)NRⁱNR^eR^f、C₁～C₅-アルキレン-OR^a、C₁～C₅-アルキレン-CN、C₁～C₅-アルキレン-C(Y)R^b、C₁～C₅-アルキレン-C(Y)OR^c、C₁～C₅-アルキレン-NR^eR^f、C₁～C₅-アルキレン-C(Y)NR^gR^h、C₁～C₅-アルキレン-S(O)_mR^d、C₁～C₅-アルキレン-S(O)_mNR^eR^f、C₁～C₅-アルキレン-NRⁱNR^eR^f、ヘテロシクリル、ヘタリール、C₃～C₁₀-シクロアルキル、C₃～C₁₀-シクロアルケニル、ヘテロシクリル-C₁～C₅-アルキル、ヘタリール-C₁～C₅-アルキル、C₃～C₁₀-シクロアルキル-C₁～C₅-アルキル、C₃～C₁₀-シクロアルケニル-C₁～C₅-アルキル、フェニル-C₁～C₅-アルキル、又はフェニルであり、最後に挙げた10個の基の環は、非置換であってもよく、又は1個、2個、3個、4個若しくは5個の同一若しくは異なる置換基R^yを有していてもよく、かつ
R^a、R^b、R^cは、互いに独立して、H、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₃～C₆-シクロアルキル、C₃～C₆-シクロアルキルメチル、C₃～C₆-ハロシクロアルキル、C₂～C₄-アルケニル、C₂～C₄-ハロアルケニル、C₂～C₄-アルキニル、C₁～C₄-アルコキシ-C₁～C₄-アルキル、ヘテロシクリル、ヘテロシクリル-C₁～C₄-アルキル、フェニル、ヘタリール、フェニル-C₁～C₄-アルキル及びヘタリール-C₁～C₄-アルキルから選択され、最後に挙げた6個の基における環は、非置換であってもよく、又は互いに独立してハロゲン、CN、NO₂、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₁～C₄-アルコキシ及びC₁～C₄-ハロアルコキシから選択される1個、2個、3個、4個若しくは5個の置換基を有していてもよく、
R^dは、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₃～C₆-シクロアルキル、C₃～C₆-シクロアルキルメチル、C₃～C₆-ハロシクロアルキル、C₂～C₄-アルケニル、C₂～C₄-ハロアルケニル、C₂～C₄-アルキニル、C₁～C₄-アルコキシ-C₁～C₄-アルキル、ヘテロシクリル、ヘテロシクリル-C₁～C₄-アルキル、フェニル、ヘタリール、フェニル-C₁～C₄-アルキル及びヘタリール-C₁～C₄-アルキルから選択され、最後に挙げた6個の基における環は、非置換であってもよく、又は互いに独立してハロゲン、CN、NO₂、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₁～C₄-アルコキシ、及びC₁～C₄-ハロアルコキシから選択される1個、2個、3個、4個若しくは5個の置換基を有していてもよく、
R^e、R^fは、互いに独立して、H、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₃～C₆-シクロアルキル、C₃～C₆-シクロアルキルメチル、C₃～C₆-ハロシクロアルキル、C₂～C₄-アルケニル、C₂～C₄-ハロアルケニル、C₂～C₄-アルキニル、C₁～C₄-アルコキシ-C₁～C₄-アルキル、C₁～C₄-アルキルカルボニル、C₁～C₄-ハロアルキルカルボニル、C₁～C₄-アルキルスルホニル、C₁～C₄-ハロアルキルスルホニル、ヘテロシクリル、ヘテロシクリル-C₁～C₄-アルキル、ヘテロシクリルカルボニル、ヘテロシクリルスルホニル、フェニル、フェニルカルボニル、フェニルスルホニル、ヘタリール、ヘタリールカルボニル、ヘタリールスルホニル、フェニル-C₁～C₄-アルキル及びヘタリール-C₁～C₄-アルキルから選択され、最後に挙げた12個の基における環は、非置換であってもよく、又は互いに独立してハロゲン、CN、NO₂、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₁～C₄-アルコキシ及びC₁～C₄-ハロアルコキシから選択される1個、2個、3個、4個若しくは5個の置換基を有していてもよく、或いは
R^e及びR^fは、それらが結合している窒素原子と一緒に、環員原子としてO、S及びNから選択されるさらなるヘテロ原子を有していてよい5員又は6員の飽和又は不飽和の複素環を形成し、複素環は、非置換であってもよく、又は互いに独立してハロゲン、CN、NO₂、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₁～C₄-アルコキシ及びC₁～C₄-ハロアルコキシから選択される1個、2個、3個、4個若しくは5個の置換基を有していてもよく、
R^g、R^hは、互いに独立して、H、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₃～C₆-シクロアルキル、C₃～C₆-ハロシクロアルキル、C₂～C₄-アルケニル、C₂～C₄-ハロアルケニル、C₂～C₄-アルキニル、C₁～C₄-アルコキシ-C₁～C₄-アルキル、ヘテロシクリル、ヘテロシクリル-C₁～C₄-アルキル、フェニル、ヘタリール、フェニル-C₁～C₄-アルキル及びヘタリール-C₁～C₄-アルキルから選択され、最後に挙げた6個の基における環は、非置換であってもよく、又は互いに独立してハロゲン、CN、NO₂、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₁～C₄-アルコキシ及びC₁～C₄-ハロアルコキシから選択される1個、2個、3個、4個若しくは5個の置換基を有していてもよく、
Rⁱは、H、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₃～C₆-シクロアルキル、C₃～C₆-シクロアルキルメチル、C₃～C₆-ハロシクロアルキル、C₂～C₄-アルケニル、C₂～C₄-ハロアルケニル、C₂～C₄-アルキニル、C₁～C₄-アルコキシ-C₁～C₄-アルキル、フェニル及びフェニル-C₁～C₄-アルキルから選択され、最後に挙げた2個の基におけるフェニル環は、非置換であってもよく、又は互いに独立してハロゲン、CN、NO₂、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₁～C₄-アルコキシ及びC₁～C₄-ハロアルコキシから選択される1個、2個、3個、4個若しくは5個の置換基を有していてもよく、
R^xは、CN、NO₂、C₁～C₄-アルコキシ、C₁～C₄-ハロアルコキシ、S(O)_mR^d、S(O)_mNR^eR^f、C₁～C₁₀-アルキルカルボニル、C₁～C₄-ハロアルキルカルボニル、C₁～C₄-アルコキシカルボニル、C₁～C₄-ハロアルコキシカルボニル、C₃～C₆-シクロアルキル、5員から7員のヘテロシクリル、5員又は6員のヘタリール、フェニル、C₃～C₆-シクロアルコキシ、3員から6員のヘテロシクリルオキシ及びフェノキシから選択され、最後に挙げた7個の基は、非置換であってもよく、又は1個、2個、3個、4個又は5個のR^y基を有していてもよく、
R^yは、ハロゲン、CN、NO₂、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₁～C₄-アルコキシ、C₁～C₄-ハロアルコキシ、S(O)_mR^d、S(O)_mNR^eR^f、C₁～C₄-アルキルカルボニル、C₁～C₄-ハロアルキルカルボニル、C₁～C₄-アルコキシカルボニル、C₁～C₄-ハロアルコキシカルボニル、C₃～C₆-シクロアルキル、C₃～C₆-ハロシクロアルキル、C₂～C₄-アルケニル、C₂～C₄-ハロアルケニル、C₂～C₄-アルキニル及びC₁～C₄-アルコキシ-C₁～C₄-アルキルから選択され、かつ、
Yは、O又はSであり、
mは、0、1又は2であり、
X¹は、好ましくはハロゲン、N₃、p-ニトロフェノキシ及びペンタフルオロフェノキシから選択される脱離基である)
をさらに含む。

the step of converting by reacting with
(wherein R ¹ is H, C ₁ -C ₂ -alkyl or C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl,
During the ceremony,
R ² is H, halogen, CN, NO ₂ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl or C ₂ -C ₁₀ -alkynyl and the last three groups mentioned are non- may be substituted, may be partially or fully halogenated, or may have 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 and the last five mentioned groups may be unsubstituted or R ^y and R ^x groups may have 1, 2, 3, 4 or 5 identical or different substituents selected from
R ³ is H, halogen, CN, NO ₂ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl or C ₂ -C ₁₀ -alkynyl, the last three groups mentioned being non- may be substituted, may be partially or fully halogenated, or may have 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 and the last five mentioned groups may be unsubstituted or R ^y and R ^x groups may have 1, 2, 3, 4 or 5 identical or different substituents selected from
R ^N is H, CN, NO ₂ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl or C ₂ -C ₁₀ -alkynyl and the last three mentioned groups are , may be unsubstituted, may be partially or fully halogenated, or may have 1, 2 or 3 identical or different substituents R ^x , or OR ^a , ^SRa , C(Y) ^Rb , C(Y) ^ORc , S(O) ^Rd , S(O ^{) 2Rd} , _NReRf , C ⁽ Y ^{) NRgRh} , 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 -} C5 _- alkylene-S(O ⁾ _mRd , C1-C5-alkylene _- S ⁽ O ^{) mNReRf} , C1- ^C5 _- ^alkylene _{- NRiNReRf} , heterocyclyl, hetaryl, C3-C10-cycloalkyl, C3-C10 _- cycloalkenyl, heterocyclyl-C1 _- C5 _- alkyl, hetaryl _- C1 _- C5 _- alkyl _, C3 _- C10 _- cycloalkyl _- C ₁ -C ₅ -alkyl, C ₃ -C ₁₀ -cycloalkenyl-C ₁ -C ₅ -alkyl, phenyl-C ₁ -C ₅ -alkyl or phenyl, the ring of the last 10 groups being , may be unsubstituted or may have 1, 2, 3, 4 or 5 identical or different substituents R ^y , and
R ^a , R ^b , R ^c are independently of each other H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl methyl, C3-C6-halocycloalkyl, _{C2 - C4 -} alkenyl, _C2 -C4-haloalkenyl, _C2 - _{C4 -} alkynyl, C1- _{C4 -} alkoxy-C1 _{- C4} -alkyl, heterocyclyl, heterocyclyl-C ₁ -C ₄ -alkyl, phenyl, hetaryl, phenyl-C ₁ -C ₄ -alkyl and hetaryl-C ₁ -C ₄ -alkyl, the last six groups The rings in may be unsubstituted or independently of each other halogen, CN, NO ₂ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy and C ₁ . optionally having 1, 2, 3, ₄ or 5 substituents selected from -C4-haloalkoxy,
R ^d is 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 - _C4 -alkenyl, _C2 -C4-haloalkenyl, _C2 - _{C4 -} alkynyl, C1- _C4 -alkoxy-C1 _{- C4 -} alkyl, heterocyclyl, heterocyclyl-C1 _{- C4-} the rings in the last-mentioned six groups may be unsubstituted or selected from alkyl, phenyl, hetaryl, phenyl-C ₁ -C ₄ -alkyl and hetaryl-C ₁ -C ₄ -alkyl; one selected independently from each other 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 , optionally having 2, 3, 4 or 5 substituents,
R ^e , R ^f are independently of each other H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkylmethyl, C ₃ -C6- _{halocycloalkyl} , _C2 - _C4 -alkenyl, _C2 -C4-haloalkenyl, _C2 - _{C4 -} alkynyl, C1- _C4 -alkoxy-C1 _{- C4 -} alkyl, C1- _{C4 -} alkylcarbonyl, C1- _{C4 -} haloalkylcarbonyl, C1- _{C4 -} alkylsulfonyl, C1- _{C4 -} haloalkylsulfonyl, heterocyclyl, heterocyclyl-C1 _{- C4} -alkyl, heterocyclylcarbonyl , heterocyclylsulfonyl, phenyl, phenylcarbonyl, phenylsulfonyl, hetaryl, hetarylcarbonyl, hetarylsulfonyl, phenyl-C ₁ -C ₄ -alkyl and hetaryl-C ₁ -C ₄ -alkyl, the last-mentioned 12 The rings in each group may be unsubstituted or independently of each other halogen, CN, NO ₂ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy and 1, 2, 3, 4 or 5 substituents selected from C ₁ -C ₄ -haloalkoxy, or
R ^e and R ^f , together with the nitrogen atom to which they are attached, are 5- or 6-membered saturated or unsaturated groups optionally having a further heteroatom selected from O, S and N as ring member atoms. Forming a saturated heterocyclic ring, the heterocyclic ring may be unsubstituted or independently of one another halogen, CN, NO ₂ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ optionally has 1, 2, 3, ₄ or 5 substituents selected from -C4-alkoxy and C1- _{C4 -} haloalkoxy,
R ^g , R ^h are independently of each other H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -halocycloalkyl, C ₂ - _C4 -alkenyl, _C2 -C4-haloalkenyl, _C2 - _{C4 -} alkynyl, C1- _C4 -alkoxy-C1 _{- C4 -} alkyl, heterocyclyl, heterocyclyl-C1 _{- C4-} the rings in the last-mentioned six groups may be unsubstituted or selected from alkyl, phenyl, hetaryl, phenyl-C ₁ -C ₄ -alkyl and hetaryl-C ₁ -C ₄ -alkyl; one selected independently from each other from halogen, CN, NO2, C1 _{- C4 -} alkyl, C1- _{C4 -} haloalkyl, C1- _{C4 -} alkoxy and C1- _{C4 -} haloalkoxy, optionally having 2, 3, 4 or 5 substituents,
R ⁱ is 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 ₁ -C The phenyl rings in the last two mentioned groups, selected from ₄ -alkyl, may be unsubstituted or independently of _each other halogen, CN, NO2, C1 _{- C4 -} alkyl, C1 It may have 1, 2, 3, ₄ or 5 substituents selected from -C4-haloalkyl, C1- _{C4 -} alkoxy and C1- _{C4 -} haloalkoxy. ,
^Rx is CN, NO2, C1 _{- C4 -} alkoxy, C1 _{- C4 -} haloalkoxy, S(O) _mRd , S ⁽ O ^{) mNReRf} , C1 _{- C10-} alkylcarbonyl, C1- _{C4 -} haloalkylcarbonyl, C1- _{C4 -} alkoxycarbonyl, C1 _{- C4 - haloalkoxycarbonyl} , C3-C6-cycloalkyl, 5- to 7-membered heterocyclyl, 5-membered or 6-membered hetaryl, phenyl, C3-C6-cycloalkoxy, _3- to ₆ -membered heterocyclyloxy and phenoxy, the last-mentioned 7 groups optionally being unsubstituted, or optionally having 1, 2, 3, 4 or 5 R ^y groups,
R ^y is 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 , C ₁ -C ₄ -alkylcarbonyl, C ₁ -C ₄ -haloalkylcarbonyl, C ₁ -C ₄ -alkoxycarbonyl, C ₁ -C ₄ -haloalkoxycarbonyl, C ₃ -C6-cycloalkyl, C3-C6- _{halocycloalkyl} , _{C2 - C4 -} alkenyl, _C2 - _C4 -haloalkenyl, _C2 - _{C4 -} alkynyl and C1- _C4 -alkoxy is selected from -C1 _{- C4} -alkyl, and
Y is O or S,
m is 0, 1 or 2;
X ¹ is preferably a leaving group selected from halogen, N ₃ , p-nitrophenoxy and pentafluorophenoxy)
further includes

In a preferred embodiment,
^R1 is _{CH2CH3 ;}
R ² is C ₁ -C ₄ -alkyl which may be unsubstituted or partially or fully halogenated,
R3 is H ^,
RN is ^{a -CR4R5R6 group} , and
R ⁴ is C ₁ -C ₄ -alkyl which may be unsubstituted, partially or fully halogenated or may carry 1 or 2 identical or different substituents R ^x (R ^x is selected from CN and C(O)NH ₂ ) and C which may be unsubstituted or may have 1, 2 or 3 identical or different substituents R ^y ₃ -C6 _- cycloalkyl ( ^Ry is selected from halogen, CN and C(O) _NH2 ),
R ⁵ is C 1 -C 4 ^-alkyl (C ₁ -C ₄ -alkyl ( R ^x is selected from CN and C(O)NH ₂ ) and C ₃ which may be unsubstituted or may carry 1, 2 or 3 identical or different substituents R ^y _-C6 -cycloalkyl ( ^Ry is selected from halogen, CN and C(O) _NH2 );
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 carbocyclic ring which may be partially or fully substituted with R j ;} is selected from halogen, CN and C(O) _NH2 ;
^R6 is H,
X ¹ is preferably a leaving group selected from halogen, N ₃ , p-nitrophenoxy and pentafluorophenoxy, particularly preferably chlorine.

^In a more ^preferred embodiment, ^RN is ^-CR4R5R6 ,
^R1 is _{CH2CH3 ;}
^R2 is _CH3 , R3 is H, ^R4 is _{CH3 ,} ^R5 is _CH3 and ^R6 is H, or
^R2 is _CH3 , R3 is H, ^R4 is _{CF3 ,} ^R5 is _CH3 and ^R6 is H, or
^R2 is _CH3 , R3 is H, ^R4 is CH ⁽ _CH3 ) _{2 ,} R5 is _CH3 and ^R6 is H, or
^R2 is _CH3 , R3 is H, ^R4 is _{CHFCH3 ,} ^R5 is _CH3 and ^R6 is H _, or ^R2 is _CH3 and R3 is H, ^R4 is ^{1 -} CN _{- cC3H4} , R5 is _CH3 and R6 is H, or
^R2 is _{CH3 ,} R3 is H, ^R4 is ^{1 -} C(O) _{NH2 - cC3H4} , R5 is _CH3 and R6 is H, or or
^R2 is _{CH3 , R3} is H, ^R4 and _{R5 together are} ^{CH2CH2CF2CH2CH2} , _R6 is H, ^X1 is preferably ^halogen , N ₃ , p-nitrophenoxy and pentafluorophenoxy, preferably chlorine.

Regarding the reaction conditions for step (v) reference is made to WO 2009/027393 and WO 2010/034737.

In the following, preferred embodiments for method B of the invention are provided. It is to be understood that the preferred embodiments of method B of the present invention described above and those further exemplified below are to be understood as preferred alone or in combination with each other.

As already indicated above, the present invention provides, in a second aspect, (a) a dichloropyridazineamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloro pyridazine amine compounds or their salts, tautomers or N-oxides, or (c) a mixture of (a) and (b)

を、
式II

of,
Formula II

の化合物とPOCl₃とを反応させるステップ、及び
結果として得られる粗反応生成物とアミン化合物R¹-NH₂又はその塩とを反応させるステップ
(式中、R¹は、H、C₁～C₂-アルキル又はC₁～C₂-アルコキシ-C₁～C₂-アルキルである)
を含むワンポット反応で製造する方法Bに関する。

with POCl3 _, and reacting the resulting crude reaction product with the amine compound R1 ^- _NH2 or a salt thereof.
(wherein R ¹ is H, C ₁ -C ₂ -alkyl or C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl)
It relates to method B, which is produced in a one-pot reaction containing

The underlying reaction steps of Method B correspond to steps (ii)+(iii) in the above reaction sequence.

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

As already indicated above, it should be understood that the compounds of formula II may also exist in the form of their pyridazone tautomers.

It should be 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 ^R1 in the compounds of _formula IVa and IVb and the amine compounds R1 ^- _NH2 is preferably selected from the group consisting of _{CH3 , CH2CH3} and _CH2OCH3 .

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

In a particularly preferred embodiment, a mixture of (a) and ₍ b) is obtained and R1 in the compounds of formula IVa and IVb and the amine compound ^{R1 -} _NH2 is _{CH3 , CH2CH3} and _CH2OCH3 is selected from the group consisting of _, preferably _CH2CH3 .

The reaction conditions for the subsequent steps (ii) and (iii) in the one-pot reaction as defined above without isolation of the intermediately obtained compound of formula III are already described above. provided.

In a preferred embodiment of method B, the method comprises step (i), ie formula II

の化合物を、
ムコクロル酸(I)

a compound of
Mucochloric acid (I)

とヒドラジン又はその塩とを反応させることによって製造するステップをさらに含む。

and hydrazine or a salt thereof.

The reaction conditions for this reaction step (i) have already been provided above.

In another preferred embodiment of method B, the method comprises step (iv), i.e. (a) a dichloropyridazineamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) formula IVb or (c) a mixture of (a) and (b) with a pyridazineamine compound of Formula V or a salt, tautomer or N-oxide thereof, of Formula V, or a salt, tautomer or N-oxide thereof oxide

に、
(a)式IVaのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(b)式IVbのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(c) (a)と(b)の混合物

to the
(a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c ) a mixture of (a) and (b)

と水素とを水素化触媒の存在下で反応させることによって変換するステップ
(式中、R¹は、上記で定義されている通りである)
をさらに含み、
場合により、ステップ(v)、即ち、式Vのピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシドを、式VIIの化合物又はその立体異性体、塩、互変異性体若しくはN-オキシド

and hydrogen by reacting in the presence of a hydrogenation catalyst
(wherein R ¹ is as defined above)
further comprising
Optionally, in step (v), i.e., the pyridazineamine compound of formula V or a salt, tautomer or N-oxide thereof, is treated with a compound of formula VII or a stereoisomer, salt, tautomer or N-oxide thereof.

に、
式Vのピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド

to the
Pyridazineamine compounds of formula V or salts, tautomers or N-oxides thereof

と、式VIの化合物又はその立体異性体、塩、互変異性体若しくはN-オキシド

and a compound of formula VI or a stereoisomer, salt, tautomer or N-oxide thereof

とを反応させることによって変換するステップ
(式中、R¹は、上記で定義されている通りであり、
式中、R²、R³、R^N及びX¹は、上記で定義されている通りである)
をさらに含む。

the step of converting by reacting with
(wherein R ¹ is as defined above,
wherein R ² , R ³ , R ^N and X ¹ are as defined above)
further includes

Preferred embodiments and reaction conditions for reaction steps (iv) and (v) have already been provided above in relation to method A.

In the following, preferred embodiments for method C of the invention are provided. It is to be understood that the preferred embodiments of method C of the present invention described above and those exemplified further below should be understood to be preferred alone or in combination with each other.

As already indicated above, the present invention provides, in a third aspect, (a) a dichloropyridazineamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of formula IVb. pyridazine amine compounds or their salts, tautomers or N-oxides, or (c) a mixture of (a) and (b)

を製造する方法Cであって、
式IIIの

A method C for manufacturing a
of formula III

トリクロロピリダジン化合物とアミン化合物R¹-NH₂又はその塩とを反応させるステップ
(式中、R¹は、CH₂CH₃である)
を含む方法に関し、ここで該方法は、場合により、式III

reacting a trichloropyridazine compound with an amine compound R1 ^- _NH2 or a salt thereof;
(wherein R ¹ is CH ₂ CH ₃ )
wherein the method optionally comprises formula III

のトリクロロピリダジン化合物を、
式II

the trichloropyridazine compound of
Formula II

の化合物とPOCl₃とを反応させることによって製造するステップをさらに含む。

with _POCl3 .

The underlying reaction steps of Method C include step (iii) and optionally additionally step (ii) in the above reaction sequence as separate steps.

Surprisingly, it has been found that particularly high yields in reaction step (iii) can be obtained if ethylamine is used as amine compound R1 ^- _NH2 . Furthermore, no labor intensive post-processing is required.

As already indicated above, it should be understood that the compounds of formula II may also exist in the form of their pyridazone tautomers.

It should be 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.

Reaction conditions for steps (ii) and (iii) performed separately according to Method C have already been provided above.

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

の化合物を、
ムコクロル酸(I)

a compound of
Mucochloric acid (I)

とヒドラジン又はその塩とを反応させることによって製造するステップをさらに含む。

and hydrazine or a salt thereof.

The reaction conditions for this reaction step (i) have already been provided above.

In another preferred embodiment of method C, the method comprises step (iv), i.e. (a) a dichloropyridazineamine compound of formula IVa or a salt, tautomer or N-oxide thereof, or (b) formula IVb or (c) a mixture of (a) and (b) with a pyridazineamine compound of Formula V or a salt, tautomer or N-oxide thereof, of Formula V, or a salt, tautomer or N-oxide thereof oxide

に、
(a)式IVaのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(b)式IVbのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(c) (a)と(b)の混合物

to the
(a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c ) a mixture of (a) and (b)

と水素とを水素化触媒の存在下で反応させることによって変換するステップ
(式中、R¹は、上記で定義されている通りである)
をさらに含み、
場合により、ステップ(v)、即ち、式Vのピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシドを、式VIIの化合物又はその立体異性体、塩、互変異性体若しくはN-オキシド

and hydrogen by reacting in the presence of a hydrogenation catalyst
(wherein R ¹ is as defined above)
further comprising
Optionally, in step (v), i.e., the pyridazineamine compound of formula V or a salt, tautomer or N-oxide thereof, is treated with a compound of formula VII or a stereoisomer, salt, tautomer or N-oxide thereof.

に、
式Vのピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド

to the
Pyridazineamine compounds of formula V or salts, tautomers or N-oxides thereof

と式VIの化合物又はその立体異性体、塩、互変異性体若しくはN-オキシド

and a compound of formula VI or a stereoisomer, salt, tautomer or N-oxide thereof

とを反応させることによって変換するステップ
(式中、R¹は、上記で定義されている通りであり、
式中、R²、R³、R^N及びX¹は、上記で定義されている通りである)
をさらに含む。

the step of converting by reacting with
(wherein R ¹ is as defined above,
wherein R ² , R ³ , R ^N and X ¹ are as defined above)
further includes

Preferred embodiments and reaction conditions for reaction steps (iv) and (v) have already been provided above in connection with method A.

In the following, preferred embodiments of method D according to the invention are provided. It is to be understood that the preferred embodiments of method D of the present invention described above and those further exemplified below are to be understood as preferred alone or in combination with each other.

As already indicated above, the present invention provides, in a further aspect, compounds of formula VII ^* or their stereoisomers, salts, tautomers or N-oxides

の製造のための方法であって、
式Vのピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド

A method for the manufacture of
Pyridazineamine compounds of formula V or salts, tautomers or N-oxides thereof

と式VI^*の化合物又はその立体異性体、塩、互変異性体若しくはN-オキシド

and a compound of formula VI ^* or a stereoisomer, salt, tautomer or N-oxide thereof

とを反応させるステップ
(式中、
R¹はCH₂CH₃であり、式中
R²はCH₃であり、R₃はHであり、R⁴はCH₃であり、R⁵はCH₃であり、R⁶はHである、又は
R²はCH₃であり、R₃はHであり、R⁴はCF₃であり、R⁵はCH₃であり、R⁶はHである、又は
R²はCH₃であり、R₃はHであり、R⁴はCH(CH₃)₂であり、R⁵はCH₃であり、R⁶はHである、又はR²はCH₃であり、R₃はHであり、R⁴はCHFCH₃であり、R⁵はCH₃であり、R⁶はHである、又は
R²はCH₃であり、R₃はHであり、R⁴は1-CN-cC₃H₄であり、R⁵はCH₃であり、R⁶はHである、又は
R²はCH₃であり、R₃はHであり、R⁴は1-C(O)NH₂-cC₃H₄であり、R⁵はCH₃であり、R⁶はHである、又は
R²はCH₃であり、R₃はHであり、R⁴及びR⁵は一緒にCH₂CH₂CF₂CH₂CH₂であり、R⁶はHであり、式中
X¹は、好ましくはハロゲン、N₃、p-ニトロフェノキシ及びペンタフルオロフェノキシから選択される脱離基であり、特に好ましくは塩素である)
を含む方法Dに関する。

the step of reacting with
(In the formula,
^R1 is _{CH2CH3 ,} where
^R2 is _CH3 , R3 is H, ^R4 is _{CH3 ,} ^R5 is _CH3 and ^R6 is H, or
^R2 is _CH3 , R3 is H, ^R4 is _{CF3 ,} ^R5 is _CH3 and ^R6 is H, or
^R2 is _CH3 , R3 is H, ^R4 is CH ⁽ _CH3 ) ₂ , R5 is _CH3 , ^R6 is H _, or ^R2 is _CH3 , R3 is H, ^R4 is _{CHFCH3 ,} ^R5 is _CH3 and ^R6 is H, or
^R2 is _{CH3 ,} R3 is H, ^R4 is ₁ ^- CN ^- _cC3H4 , R5 is _CH3 and R6 is H, or
^R2 is _{CH3 ,} R3 is H, ^R4 is ^{1 -} C(O) _{NH2 - cC3H4} , R5 is _CH3 and R6 is H, or
^R2 is _{CH3 , R3} is ^H , ^R4 and _{R5 together are} ^{CH2CH2CF2CH2CH2} , _R6 is H, wherein
X ¹ is preferably a leaving group selected from halogen, N ₃ , p-nitrophenoxy and pentafluorophenoxy, particularly preferably chlorine)
Regarding method D comprising:

The underlying reaction step of Method D is encompassed by step (v) of the above reaction sequence.

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

In a more preferred embodiment, the method further comprises step (iii) and optionally step (ii), wherein steps (ii) and (iii) are separately performed via isolation of the compound of formula III. , or together in a one-pot reaction.

In a more preferred embodiment, the method further comprises step (i).

Further details regarding steps (i), (ii), (iii) and (iv) are provided above.

As already indicated above, the present invention provides, in another aspect, a dichloropyridazineamine compound of formula IVa or a salt, tautomer or N-oxide thereof

(式中、R¹はCH₂CH₃である)
或いは式IVbのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド

(wherein R ¹ is CH ₂ CH ₃ )
or a dichloropyridazineamine compound of formula IVb or a salt, tautomer or N-oxide thereof

(式中、R¹はCH₂CH₃である)
に関する。

(wherein R ¹ is CH ₂ CH ₃ )
Regarding.

In a further aspect, the invention provides a dichloropyridazineamine compound of formula IVa, or a salt, tautomer or N-oxide thereof, as defined above, i.e., wherein ^R1 is _CH2CH3 at _each occurrence and dichloropyridazineamine compounds of formula IVb or mixtures of salts, tautomers or N-oxides thereof.

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

Typically, dichloropyridazineamine compounds of formula IVa or salts, tautomers or N-oxides thereof and of formula IVb as defined above, i.e. ^R1 is _CH2CH3 in _each instance. The dichloropyridazineamine compounds or mixtures of salts, tautomers or N-oxides thereof can be obtained by Method B or C as described herein. The mixture comprises components (a) a dichloropyridazineamine compound of Formula IVa or its salts, tautomers or N-oxides and (b) a dichloropyridazineamine compound of Formula IVb or its salts, tautomers or N- The oxides can be separated by separation techniques known to those skilled in the art, eg by column chromatography. However, separation of the two components is not required to prepare the pyridazine amine compounds of formula V as both components are suitable starting materials for the dehalogenation/hydrogenation reaction.

In said mixture, components (a) a dichloropyridazineamine compound of Formula IVa or its salts, tautomers or N-oxides and (b) a dichloropyridazineamine compound of Formula IVb or its salts, tautomers or N- the oxides in any ratio, preferably 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 it can be present in a weight ratio range of 1:1.

I. Characterization Characterization can be performed by coupled high performance liquid chromatography/mass spectroscopy (HPLC/MS), by NMR, or by their melting points.

HPLC: Agilent Extend 1.8 μm C18 4.6×100 mm, mobile phase: A: water + 0.1% _H3PO4 , B: acetonitrile (MeCN) + 0.1% _{H3PO4 ,} gradient: 5-95% A in ₁₀ minutes, 0-10 min 5:95 A:B then gradient 10-10.1 min to 95:5 A:B flow rate: 1.2 ml/min at 60° C. in 10 min.

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

Abbreviations used: h is hour, min is minute, room temperature is 20-25°C.

II.Manufacturing example
1. Preparation of a mixture of 3,4-dichloro-5-ethylaminopyridazine and 3,5-dichloro-4-ethylaminopyridazine in a one-pot procedure starting from 4,5-dichloro-3-hydroxypyridazine:
200g of 4,5-dichloro-3-hydroxypyridazine was charged into the reactor at 20°C under _N2 , _POCl3 (930g, 5eq) was added and the reaction mixture was heated to 100°C. The reaction mixture was further stirred for about 1 hour until complete conversion was achieved. Excess POCl ₃ was removed by distillation. The reaction mixture was poured into 1200 g _H2O while controlling the temperature at 30°C. Butyl acetate (1200 g) was added and the biphasic mixture was stirred for 30 minutes at 30° C., then the phases were allowed to separate. Another portion of butyl acetate (400g) was used to wash the aqueous phase. The combined organic phases were washed with 10% HCl and then _H2O .

To the mixture of trichloropyridazine in butyl acetate was added an aqueous solution of ethylamine at a concentration of 70 wt.-% ethylamine (234 g, 3 eq) based on the total weight of the solution at 35°C. The reaction was held at 45° C. for 3 hours (or until complete conversion was observed). The phases were separated at 40°C and the organic phase was washed once with _H2O . The combined aqueous phases were extracted once with butyl acetate. The reaction mixture was concentrated by distilling butyl acetate from the combined organic phases (15 mbar, 35° C.). 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 rest of the product was isolated by recrystallization of the crude material from MTBE.

2. Preparation of 4-ethylaminopyridazine:
600 g (3.09 mol) of a mixture of 3,4-dichloro-5-ethylaminopyridazine and 3,5-dichloro-4-ethylaminopyridazine were dissolved in EtOH (3.5 liters). 15 g (0.01 mol) of 10% Pd/C was added and the pressure reactor was purged with nitrogen. _The pressure reactor was pressurized to 0.2 bar with H2 and heated to 35°C. The reaction was exothermic so the temperature was controlled at 55°C for 4 hours. The pressure was then released and the reactor was purged with _N2 . The catalyst was removed by filtering the reaction mixture at room temperature. The catalyst can be reused in the next batch without purification.

を製造するための方法であって、
(a)式IVaのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(b)式IVbのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(c) (a)と(b)の混合物

と水素とを水素化触媒の存在下で反応させるステップ
(式中、
R¹はH、C₁～C₂-アルキル又はC₁～C₂-アルコキシ-C₁～C₂-アルキルである)
を含む方法。
（付記２）
反応をHClスカベンジャーの非存在下で行う、付記1に記載の方法。
（付記３）
HClスカベンジャーは水素化触媒の除去後に添加し、該HClスカベンジャーは好ましくは水なしで提供される、付記1又は2に記載の方法。
（付記４）
HClスカベンジャーが、アルカリ金属及びアルカリ土類金属水酸化物、アルカリ金属及びアルカリ土類金属酸化物、アルカリ金属及びアルカリ土類金属水素化物、アルカリ金属アミド、アルカリ金属及びアルカリ土類金属炭酸塩、アルカリ金属重炭酸塩、アルカリ金属アルキル、アルキルマグネシウムハロゲン化物、アルカリ金属及びアルカリ土類金属アルコラートを含む塩基、第3級アミン、ピリジン、二環式アミン、アンモニア、及び第1級アミンを含む窒素含有塩基;並びにその組合せ;酢酸ナトリウム及び/又はギ酸アンモニウムを含む緩衝液;イミダゾールを含むイオン性液体の前駆体;並びにその組合せからなる群から選択される、付記1から3のいずれか一項に記載の方法。
（付記５）
水素化触媒が、担体上の白金又はパラジウム、ラネーニッケル及びラネーコバルトからなる群から選択され、好ましくは炭素上の白金又はパラジウムである、付記1から4のいずれか一項に記載の方法。
（付記６）
R¹がCH₂CH₃である、付記1から5のいずれか一項に記載の方法。
（付記７）
(a)式IVaのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(b)式IVbのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(c) (a)と(b)の混合物

を、
式II

の化合物とPOCl₃とを反応させるステップ、及び
結果として得られる粗反応生成物とアミン化合物R¹-NH₂又はその塩とを反応させるステップ
(式中、R¹は付記1又は6に規定されている通りである)
を含むワンポット反応で製造するステップをさらに含む、付記1から6のいずれか一項に記載の方法。
（付記８）
(a)式IVaのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(b)式IVbのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(c) (a)と(b)の混合物

を、
式III

のトリクロロピリダジン化合物とアミン化合物R¹-NH₂又はその塩とを反応させることによって製造するステップ
(式中、R¹は、付記1又は6に規定されている通りである)
をさらに含み、
場合により、式III

のトリクロロピリダジン化合物を、
式II

の化合物とPOCl₃とを反応させることによって製造するステップをさらに含む、
付記1から6のいずれか一項に記載の方法。
（付記９）
式II

の化合物を、
ムコクロル酸(I)

とヒドラジン又はその塩とを反応させることによって製造するステップをさらに含む、付記7又は8に記載の方法。
（付記１０）
式Vのピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシドを、式VIIの化合物又はその立体異性体、塩、互変異性体若しくはN-オキシド

に、
式Vのピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド

と式VIの化合物又はその立体異性体、塩、互変異性体若しくはN-オキシド

とを反応させることによって変換するステップ
(式中、R¹は、付記1又は6に規定されている通りであり、
R²は、H、ハロゲン、CN、NO₂、C₁～C₁₀-アルキル、C₂～C₁₀-アルケニル、又はC₂～C₁₀-アルキニルであり、ここで、最後に挙げた3個の基は、非置換であってもよく、部分的若しくは完全にハロゲン化されていてもよく、又は1個、2個若しくは3個の同一若しくは異なる置換基R^xを有していてもよく、或いは
OR^a、SR^a、C(Y)R^b、C(Y)OR^c、S(O)R^d、S(O)₂R^d、NR^eR^f、C(Y)NR^gR^h、ヘテロシクリル、ヘタリール、C₃～C₁₀-シクロアルキル、C₃～C₁₀-シクロアルケニル又はフェニルであり、ここで、最後に挙げた5個の基は、非置換であってもよく、又はR^y及びR^x基から選択される1個、2個、3個、4個若しくは5個の同一若しくは異なる置換基を有していてもよく、
R³は、H、ハロゲン、CN、NO₂、C₁～C₁₀-アルキル、C₂～C₁₀-アルケニル又はC₂～C₁₀-アルキニルであり、最後に挙げた3個の基は、非置換であってもよく、部分的若しくは完全にハロゲン化されていてもよく、又は1個、2個若しくは3個の同一若しくは異なる置換基R^xを有していてもよく、或いは
OR^a、SR^a、C(Y)R^b、C(Y)OR^c、S(O)R^d、S(O)₂R^d、NR^eR^f、C(Y)NR^gR^h、ヘテロシクリル、ヘタリール、C₃～C₁₀-シクロアルキル、C₃～C₁₀-シクロアルケニル又はフェニルであり、最後に挙げた5個の基は、非置換であってもよく、又はR^y及びR^x基から選択される1個、2個、3個、4個若しくは5個の同一若しくは異なる置換基を有していてもよく、
R^Nは、H、CN、NO₂、C₁～C₁₀-アルキル、C₂～C₁₀-アルケニル又はC₂～C₁₀-アルキニルであり、最後に挙げた3個の基は、非置換であってもよく、部分的若しくは完全にハロゲン化されていてもよく、又は1個、2個若しくは3個の同一若しくは異なる置換基R^xを有していてもよく、或いはOR^a、SR^a、C(Y)R^b、C(Y)OR^c、S(O)R^d、S(O)₂R^d、NR^eR^f、C(Y)NR^gR^h、S(O)_mNR^eR^f、C(Y)NRⁱNR^eR^f、C₁～C₅-アルキレン-OR^a、C₁～C₅-アルキレン-CN、C₁～C₅-アルキレン-C(Y)R^b、C₁～C₅-アルキレン-C(Y)OR^c、C₁～C₅-アルキレン-NR^eR^f、C₁～C₅-アルキレン-C(Y)NR^gR^h、C₁～C₅-アルキレン-S(O)_mR^d、C₁～C₅-アルキレン-S(O)_mNR^eR^f、C₁～C₅-アルキレン-NRⁱNR^eR^f、ヘテロシクリル、ヘタリール、C₃～C₁₀-シクロアルキル、C₃～C₁₀-シクロアルケニル、ヘテロシクリル-C₁～C₅-アルキル、ヘタリール-C₁～C₅-アルキル、C₃～C₁₀-シクロアルキル-C₁～C₅-アルキル、C₃～C₁₀-シクロアルケニル-C₁～C₅-アルキル、フェニル-C₁～C₅-アルキル、又はフェニルであり、最後に挙げた10個の基の環は、非置換であってもよく、又は1個、2個、3個、4個若しくは5個の同一若しくは異なる置換基R^yを有していてよく、
R^a、R^b、R^cは、互いに独立して、H、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₃～C₆-シクロアルキル、C₃～C₆-シクロアルキルメチル、C₃～C₆-ハロシクロアルキル、C₂～C₄-アルケニル、C₂～C₄-ハロアルケニル、C₂～C₄-アルキニル、C₁～C₄-アルコキシ-C₁～C₄-アルキル、ヘテロシクリル、ヘテロシクリル-C₁～C₄-アルキル、フェニル、ヘタリール、フェニル-C₁～C₄-アルキル及びヘタリール-C₁～C₄-アルキルから選択され、ここで、最後に挙げた6個の基における環は、非置換であってもよく、又は互いに独立してハロゲン、CN、NO₂、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₁～C₄-アルコキシ及びC₁～C₄-ハロアルコキシから選択される1個、2個、3個、4個若しくは5個の置換基を有していてもよく、R^dは、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₃～C₆-シクロアルキル、C₃～C₆-シクロアルキルメチル、C₃～C₆-ハロシクロアルキル、C₂～C₄-アルケニル、C₂～C₄-ハロアルケニル、C₂～C₄-アルキニル、C₁～C₄-アルコキシ-C₁～C₄-アルキル、ヘテロシクリル、ヘテロシクリル-C₁～C₄-アルキル、フェニル、ヘタリール、フェニル-C₁～C₄-アルキル及びヘタリール-C₁～C₄-アルキルから選択され、最後に挙げた6個の基における環は、非置換であってもよく、又は互いに独立してハロゲン、CN、NO₂、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₁～C₄-アルコキシ及びC₁～C₄-ハロアルコキシから選択される1個、2個、3個、4個若しくは5個の置換基を有していてもよく、
R^e、R^fは、互いに独立して、H、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₃～C₆-シクロアルキル、C₃～C₆-シクロアルキルメチル、C₃～C₆-ハロシクロアルキル、C₂～C₄-アルケニル、C₂～C₄-ハロアルケニル、C₂～C₄-アルキニル、C₁～C₄-アルコキシ-C₁～C₄-アルキル、C₁～C₄-アルキルカルボニル、C₁～C₄-ハロアルキルカルボニル、C₁～C₄-アルキルスルホニル、C₁～C₄-ハロアルキルスルホニル、ヘテロシクリル、ヘテロシクリル-C₁～C₄-アルキル、ヘテロシクリルカルボニル、ヘテロシクリルスルホニル、フェニル、フェニルカルボニル、フェニルスルホニル、ヘタリール、ヘタリールカルボニル、ヘタリールスルホニル、フェニル-C₁～C₄-アルキル及びヘタリール-C₁～C₄-アルキルから選択され、最後に挙げた12個の基における環は、非置換であってもよく、又は互いに独立して、ハロゲン、CN、NO₂、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₁～C₄-アルコキシ及びC₁～C₄-ハロアルコキシから選択される1個、2個、3個、4個若しくは5個の置換基を有していてもよく、或いは
R^e及びR^fは、それらが結合している窒素原子と一緒に、環員原子としてO、S及びNから選択されるさらなるヘテロ原子を有していてよい5員又は6員の飽和又は不飽和の複素環を形成し、複素環は、非置換であってもよく、又は互いに独立してハロゲン、CN、NO₂、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₁～C₄-アルコキシ及びC₁～C₄-ハロアルコキシから選択される1個、2個、3個、4個若しくは5個の置換基を有していてもよく、
R^g、R^hは、互いに独立して、H、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₃～C₆-シクロアルキル、C₃～C₆-ハロシクロアルキル、C₂～C₄-アルケニル、C₂～C₄-ハロアルケニル、C₂～C₄-アルキニル、C₁～C₄-アルコキシ-C₁～C₄-アルキル、ヘテロシクリル、ヘテロシクリル-C₁～C₄-アルキル、フェニル、ヘタリール、フェニル-C₁～C₄-アルキル及びヘタリール-C₁～C₄-アルキルから選択され、最後に挙げた6個の基における環は、非置換であってもよく、又は互いに独立してハロゲン、CN、NO₂、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₁～C₄-アルコキシ及びC₁～C₄-ハロアルコキシから選択される1個、2個、3個、4個若しくは5個の置換基を有していてもよく、
Rⁱは、H、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₃～C₆-シクロアルキル、C₃～C₆-シクロアルキルメチル、C₃～C₆-ハロシクロアルキル、C₂～C₄-アルケニル、C₂～C₄-ハロアルケニル、C₂～C₄-アルキニル、C₁～C₄-アルコキシ-C₁～C₄-アルキル、フェニル及びフェニル-C₁～C₄-アルキルから選択され、最後に挙げた2個の基におけるフェニル環は、非置換であってもよく、又は互いに独立してハロゲン、CN、NO₂、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₁～C₄-アルコキシ及びC₁～C₄-ハロアルコキシから選択される1個、2個、3個、4個若しくは5個の置換基を有していてもよく、
R^xは、CN、NO₂、C₁～C₄-アルコキシ、C₁～C₄-ハロアルコキシ、S(O)_mR^d、S(O)_mNR^eR^f、C₁～C₁₀-アルキルカルボニル、C₁～C₄-ハロアルキルカルボニル、C₁～C₄-アルコキシカルボニル、C₁～C₄-ハロアルコキシカルボニル、C₃～C₆-シクロアルキル、5員から7員のヘテロシクリル、5員又は6員のヘタリール、フェニル、C₃～C₆-シクロアルコキシ、3員から6員のヘテロシクリルオキシ、及びフェノキシから選択され、ここで、最後に挙げた7個の基は、非置換であってもよく、又は1個、2個、3個、4個又は5個のR^y基を有していてもよく、
R^yは、ハロゲン、CN、NO₂、C₁～C₄-アルキル、C₁～C₄-ハロアルキル、C₁～C₄-アルコキシ、C₁～C₄-ハロアルコキシ、S(O)_mR^d、S(O)_mNR^eR^f、C₁～C₄-アルキルカルボニル、C₁～C₄-ハロアルキルカルボニル、C₁～C₄-アルコキシカルボニル、C₁～C₄-ハロアルコキシカルボニル、C₃～C₆-シクロアルキル、C₃～C₆-ハロシクロアルキル、C₂～C₄-アルケニル、C₂～C₄-ハロアルケニル、C₂～C₄-アルキニル及びC₁～C₄-アルコキシ-C₁～C₄-アルキルから選択され、
Yは、O又はSであり、
mは、0、1又は2であり、
X¹は、好ましくはハロゲン、N₃、p-ニトロフェノキシ及びペンタフルオロフェノキシから選択される脱離基である)
をさらに含む、付記1から9のいずれか一項に記載の方法。
（付記１１）
R¹が、CH₂CH₃であり、
R²が、非置換であってよい又は部分的若しくは完全にハロゲン化されていてよいC₁～C₄-アルキルであり、
R³が、Hであり、
R^Nが、-CR⁴R⁵R⁶基であり、
R⁴は、非置換であってよい、部分的若しくは完全にハロゲン化されていてよい又は1個若しくは2個の同一若しくは異なる置換基R^xを有していてよいC₁～C₄-アルキル(R^xは、CN及びC(O)NH₂から選択される)並びに
非置換であってよい又は1個、2個若しくは3個の同一若しくは異なる置換基R^yを有していてよいC₃～C₆-シクロアルキル(R^yは、ハロゲン、CN及びC(O)NH₂から選択される)から選択され、
R⁵は、非置換であってよい、部分的若しくは完全にハロゲン化されていてよい又は1個若しくは2個の同一若しくは異なる置換基R^xを有していてよいC₁～C₄-アルキル(R^xは、CN及びC(O)NH₂から選択される)、並びに
非置換であってよい又は1個、2個若しくは3個の同一若しくは異なる置換基R^yを有していてよいC₃～C₆-シクロアルキル(R^yは、ハロゲン、CN及びC(O)NH₂から選択される)から選択され、
或いは
R⁴及びR⁵は、それらが結合している炭素原子と一緒に、R^jによって部分的又は完全に置換されていてよい3員から12員の非芳香族飽和炭素環を形成し、ここで、R^jは、ハロゲン、CN及びC(O)NH₂から選択され、
R⁶は、Hであり、
X¹は、好ましくはハロゲン、N₃、p-ニトロフェノキシ及びペンタフルオロフェノキシから選択される脱離基であり、特に好ましくは塩素である、
付記10に記載の方法。
（付記１２）
(a)式IVaのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(b)式IVbのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(c) (a)と(b)の混合物

を、
式II

の化合物とPOCl₃とを反応させるステップ、及び
結果として得られる粗反応生成物とアミン化合物R¹-NH₂又はその塩とを反応させるステップ
(式中、R¹は、付記1又は6に規定されている通りである)
を含むワンポット反応で製造するための方法。
（付記１３）
(a)式IVaのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(b)式IVbのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(c) (a)と(b)の混合物

を製造するための方法であって、
式III

のトリクロロピリダジン化合物とアミン化合物R¹-NH₂又はその塩とを反応させるステップ(式中、R¹は、CH₂CH₃である)
を含み、
場合により、式III

のトリクロロピリダジン化合物を、
式II

の化合物とPOCl₃とを反応させることによって製造するステップをさらに含む方法。
（付記１４）
式II

の化合物を、
ムコクロル酸(I)

とヒドラジン又はその塩とを反応させることによって製造するステップをさらに含む、付記12又は13に記載の方法。
（付記１５）
(a)式IVaのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(b)式IVbのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(c) (a)と(b)の混合物を、式Vのピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド

に、
(a)式IVaのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(b)式IVbのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド、或いは(c) (a)と(b)の混合物

と水素とを水素化触媒の存在下で反応させることによって変換するステップ
(式中、R¹は、付記12又は13に規定されている通りである)
をさらに含み、
場合により、式Vのピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシドを、式VIIの化合物又はその立体異性体、塩、互変異性体若しくはN-オキシド

に、
式Vのピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド

と式VIの化合物又はその立体異性体、塩、互変異性体若しくはN-オキシド

とを反応させることによって変換するステップ
(式中、R¹は、付記12又は13に規定されている通りであり、
式中、R²、R³、R^N及びX¹は、付記10又は11に規定されている通りである)
をさらに含む、付記12から14のいずれか一項に記載の方法。
（付記１６）
式IVaのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド

(式中、R¹は、CH₂CH₃である)、
或いは式IVbのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシド

(式中、R¹は、CH₂CH₃である)。
（付記１７）
付記16に規定される式IVaのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシドと式IVbのジクロロピリダジンアミン化合物又はその塩、互変異性体若しくはN-オキシドの混合物。 In a second reactor a mixture of K ₂ CO ₃ (1 kg) and 1 liter of EtOH was produced. The reaction mixture was poured into the potassium carbonate solution over 60 minutes and the temperature was controlled at 20-25°C. The reaction mixture was further stirred for 3 hours. Salts formed in the process were filtered off. A portion of the solvent from the reaction mixture was distilled and MTBE was added to precipitate pure ethylaminopyridazine (354 g, 91% purity, 85% yield).
(Appendix)
(Appendix 1)
Pyridazineamine compounds of formula V or salts, tautomers or N-oxides thereof

A method for manufacturing a
(a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c ) a mixture of (a) and (b)

and hydrogen in the presence of a hydrogenation catalyst
(In the formula,
R ¹ is H, C ₁ -C ₂ -alkyl or C ₁ -C ₂ -alkoxy-C ₁ -C ₂ -alkyl)
method including.
(Appendix 2)
The method of Appendix 1, wherein the reaction is carried out in the absence of HCl scavenger.
(Appendix 3)
3. The method of paragraphs 1 or 2, wherein the HCl scavenger is added after removal of the hydrogenation catalyst, said HCl scavenger preferably being provided without water.
(Appendix 4)
HCl scavengers 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 Bases including metal 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 combinations thereof; buffers comprising sodium acetate and/or ammonium formate; precursors of ionic liquids comprising imidazole; and combinations thereof. Method.
(Appendix 5)
5. A process according to any one of the appendices 1 to 4, wherein the hydrogenation catalyst is selected from the group consisting of platinum or palladium on a support, Raney nickel and Raney cobalt, preferably platinum or palladium on carbon.
(Appendix 6)
6. The method of any one of clauses 1-5 _, wherein ^R1 is _CH2CH3 .
(Appendix 7)
(a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c ) a mixture of (a) and (b)

of,
Formula II

with POCl3 _, and reacting the resulting crude reaction product with the amine compound R1 ^- _NH2 or a salt thereof.
(wherein R ¹ is as defined in Appendix 1 or 6)
7. The method of any one of Appendixes 1 to 6, further comprising the step of making in a one-pot reaction comprising
(Appendix 8)
(a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c ) a mixture of (a) and (b)

of,
Formula III

by reacting a trichloropyridazine compound with an amine compound R ¹ —NH ₂ or a salt thereof
(wherein R ¹ is as defined in Appendix 1 or 6)
further comprising
Optionally, formula III

the trichloropyridazine compound of
Formula II

by reacting a compound of with _POCl3 ,
A method according to any one of appendices 1 to 6.
(Appendix 9)
Formula II

a compound of
Mucochloric acid (I)

9. The method according to appendix 7 or 8, further comprising the step of producing by reacting with hydrazine or a salt thereof.
(Appendix 10)
A pyridazine amine compound of formula V or a salt, tautomer or N-oxide thereof, a compound of formula VII or a stereoisomer, salt, tautomer or N-oxide thereof

to the
Pyridazineamine compounds of formula V or salts, tautomers or N-oxides thereof

and a compound of formula VI or a stereoisomer, salt, tautomer or N-oxide thereof

the step of converting by reacting with
(Wherein R ¹ is as defined in Appendix 1 or 6,
R ² is H, halogen, CN, NO ₂ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl, or C ₂ -C ₁₀ -alkynyl, wherein the last three The group may be unsubstituted, partially or fully halogenated, or have 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, wherein the last five mentioned groups may be unsubstituted or R ^y and optionally having 1, 2, 3, 4 or 5 identical or different substituents selected from R ^x groups,
R ³ is H, halogen, CN, NO ₂ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl or C ₂ -C ₁₀ -alkynyl, the last three groups mentioned being non- may be substituted, may be partially or fully halogenated, or may have 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 and the last five mentioned groups may be unsubstituted or R ^y and R ^x groups may have 1, 2, 3, 4 or 5 identical or different substituents selected from
R ^N is H, CN, NO ₂ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl or C ₂ -C ₁₀ -alkynyl, the last three groups mentioned being unsubstituted may be partially or fully halogenated or may have 1, 2 or 3 identical or different substituents R ^x or OR ^a , SR ^a , C(Y) ^Rb , C(Y) ^ORc , S(O) ^Rd , S(O) _2Rd , ^NReRf , C( ^{Y ) NRgRh} , S ⁽ O ₎ ^mNRe 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 ⁾ _mRd , C1 _- C5-alkylene-S ⁽ O ^{) mNReRf} , C1- ^C5 _- alkylene _{- NRiNReRf ,} heterocyclyl, ^hetaryl , C3 -C10 _- cycloalkyl, C3 _- C10 _- cycloalkenyl, heterocyclyl-C1 _- C5 _- alkyl, hetaryl-C1 _- C5 _- alkyl, C3 _- C10 _- cycloalkyl _- C1 _- C5 -alkyl, C ₃ -C ₁₀ -cycloalkenyl-C ₁ -C ₅ -alkyl, phenyl-C ₁ -C ₅ -alkyl or phenyl, the ring of the last 10 groups being unsubstituted or may have 1, 2, 3, 4 or 5 identical or different substituents R ^y ,
R ^a , R ^b , R ^c are independently of each other H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl methyl, C3-C6-halocycloalkyl, _{C2 - C4 -} alkenyl, _C2 -C4-haloalkenyl, _C2 - _{C4 -} alkynyl, C1- _{C4 -} alkoxy-C1 _{- C4} -alkyl, heterocyclyl, heterocyclyl-C ₁ -C ₄ -alkyl, phenyl, hetaryl, phenyl-C ₁ -C ₄ -alkyl and hetaryl-C ₁ -C ₄ -alkyl, wherein the last-mentioned 6 The rings in each group may be unsubstituted or independently of each other 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, wherein R ^d is C ₁ -C ₄ -alkyl, C1 _{- C4 -} haloalkyl, C3-C6 _- cycloalkyl, C3-C6-cycloalkylmethyl, C3-C6 _{- halocycloalkyl} , _{C2 - C4 -} alkenyl, _C2 - _C4 -haloalkenyl, _C2 - _{C4 -} alkynyl, C1- _C4 -alkoxy-C1 _{- C4} -alkyl, heterocyclyl, heterocyclyl-C1 _{- C4} -alkyl, phenyl, hetaryl, phenyl-C1 _- C4-alkyl The rings in the last 6 groups selected from ₄ -alkyl and hetaryl-C ₁ -C ₄ -alkyl may be unsubstituted or independently of each other halogen, CN, NO ₂ , C ₁ , 2, 3, 4 or 5 selected from ₁ - _C4 -alkyl, C1- _{C4 -} haloalkyl, C1- _C4 -alkoxy and C1- _{C4 -} haloalkoxy; may have a substituent,
R ^e , R ^f are independently of each other H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkylmethyl, C ₃ -C6- _{halocycloalkyl} , _C2 - _C4 -alkenyl, _C2 -C4-haloalkenyl, _C2 - _{C4 -} alkynyl, C1- _C4 -alkoxy-C1 _{- C4 -} alkyl, C1- _{C4 -} alkylcarbonyl, C1- _{C4 -} haloalkylcarbonyl, C1- _{C4 -} alkylsulfonyl, C1- _{C4 -} haloalkylsulfonyl, heterocyclyl, heterocyclyl-C1 _{- C4} -alkyl, heterocyclylcarbonyl , heterocyclylsulfonyl, phenyl, phenylcarbonyl, phenylsulfonyl, hetaryl, hetarylcarbonyl, hetarylsulfonyl, phenyl-C ₁ -C ₄ -alkyl and hetaryl-C ₁ -C ₄ -alkyl, the last-mentioned 12 The rings in each group may be unsubstituted or independently of each other halogen, CN, NO ₂ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ - may have 1, 2, 3, 4 or 5 substituents selected from alkoxy and C ₁ -C ₄ -haloalkoxy, or
R ^e and R ^f , together with the nitrogen atom to which they are attached, are 5- or 6-membered saturated or unsaturated groups optionally having a further heteroatom selected from O, S and N as ring member atoms. Forming a saturated heterocyclic ring, the heterocyclic ring may be unsubstituted or independently of one another halogen, CN, NO ₂ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ optionally has 1, 2, 3, ₄ or 5 substituents selected from -C4-alkoxy and C1- _{C4 -} haloalkoxy,
R ^g , R ^h are independently of each other H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -halocycloalkyl, C ₂ - _C4 -alkenyl, _C2 -C4-haloalkenyl, _C2 - _{C4 -} alkynyl, C1- _C4 -alkoxy-C1 _{- C4 -} alkyl, heterocyclyl, heterocyclyl-C1 _{- C4-} the rings in the last-mentioned six groups may be unsubstituted or selected from alkyl, phenyl, hetaryl, phenyl-C ₁ -C ₄ -alkyl and hetaryl-C ₁ -C ₄ -alkyl; one selected independently from each other from halogen, CN, NO2, C1 _{- C4 -} alkyl, C1- _{C4 -} haloalkyl, C1- _{C4 -} alkoxy and C1- _{C4 -} haloalkoxy, optionally having 2, 3, 4 or 5 substituents,
R ⁱ is 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 ₁ -C The phenyl rings in the last two mentioned groups, selected from ₄ -alkyl, may be unsubstituted or independently of _each other halogen, CN, NO2, C1 _{- C4 -} alkyl, C1 It may have 1, 2, 3, ₄ or 5 substituents selected from -C4-haloalkyl, C1- _{C4 -} alkoxy and C1- _{C4 -} haloalkoxy. ,
^Rx is CN, NO2, C1 _{- C4 -} alkoxy, C1 _{- C4 -} haloalkoxy, S(O) _mRd , S ⁽ O ^{) mNReRf} , C1 _{- C10-} alkylcarbonyl, C1- _{C4 -} haloalkylcarbonyl, C1- _{C4 -} alkoxycarbonyl, C1 _{- C4 - haloalkoxycarbonyl} , C3-C6-cycloalkyl, 5- to 7-membered heterocyclyl, 5-membered or 6-membered hetaryl, phenyl, C3-C6-cycloalkoxy, _3- to ₆ -membered heterocyclyloxy, and phenoxy, wherein the last seven named groups are unsubstituted or may have 1, 2, 3, 4 or 5 R ^y groups,
R ^y is 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 , C ₁ -C ₄ -alkylcarbonyl, C ₁ -C ₄ -haloalkylcarbonyl, C ₁ -C ₄ -alkoxycarbonyl, C ₁ -C ₄ -haloalkoxycarbonyl, C ₃ -C6-cycloalkyl, C3-C6- _{halocycloalkyl} , _{C2 - C4 -} alkenyl, _C2 - _C4 -haloalkenyl, _C2 - _{C4 -} alkynyl and C1- _C4 -alkoxy - is selected from -C1 _{- C4} -alkyl;
Y is O or S,
m is 0, 1 or 2;
X ¹ is preferably a leaving group selected from halogen, N ₃ , p-nitrophenoxy and pentafluorophenoxy)
10. The method of any one of clauses 1-9, further comprising:
(Appendix 11)
^R1 is _{CH2CH3 ,}
R ² is C ₁ -C ₄ -alkyl which may be unsubstituted or partially or fully halogenated,
R3 is H ^,
RN is a -CR ^{4 R 5} R ⁶ group,
R ⁴ is C 1 -C 4 ^-alkyl (C ₁ -C ₄ -alkyl ( R ^x is selected from CN and C(O)NH ₂ ⁾ and C ₃ to C6 _- cycloalkyl ( ^Ry is selected from halogen, CN and C(O) _NH2 );
R ⁵ is C 1 -C 4 ^-alkyl (C ₁ -C ₄ -alkyl ( R ^x is selected from CN and C(O)NH ₂ ) and C ₃ which may be unsubstituted or may carry 1, 2 or 3 identical or different substituents R ^y _-C6 -cycloalkyl ( ^Ry is selected from halogen, CN and C(O) _NH2 );
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 carbocyclic ring which may be partially or fully substituted with R ^j , wherein , R ^j are selected from halogen, CN and C(O)NH ₂ ;
^R6 is H,
X ¹ is preferably a leaving group selected from halogen, N ₃ , p-nitrophenoxy and pentafluorophenoxy, particularly preferably chlorine,
The method described in Appendix 10.
(Appendix 12)
(a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c ) a mixture of (a) and (b)

of,
Formula II

with POCl3 _, and reacting the resulting crude reaction product with the amine compound R1 ^- _NH2 or a salt thereof.
(wherein R ¹ is as defined in Appendix 1 or 6)
A method for producing in a one-pot reaction comprising:
(Appendix 13)
(a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c ) a mixture of (a) and (b)

A method for manufacturing a
Formula III

with an amine compound R1 ^- _NH2 or a salt thereof _, wherein ^R1 is _CH2CH3 .
including
Optionally, formula III

the trichloropyridazine compound of
Formula II

with _POCl3 .
(Appendix 14)
Formula II

a compound of
Mucochloric acid (I)

14. The method according to appendix 12 or 13, further comprising the step of producing by reacting with hydrazine or a salt thereof.
(Appendix 15)
(a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c ) a mixture of (a) and (b) to form a pyridazineamine compound of Formula V or a salt, tautomer or N-oxide thereof;

to the
(a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c ) a mixture of (a) and (b)

and hydrogen by reacting in the presence of a hydrogenation catalyst
(wherein R ¹ is as defined in Appendix 12 or 13)
further comprising
Optionally, the pyridazine amine compound of Formula V or a salt, tautomer or N-oxide thereof is combined with a compound of Formula VII or a stereoisomer, salt, tautomer or N-oxide thereof.

to the
Pyridazineamine compounds of formula V or salts, tautomers or N-oxides thereof

and a compound of formula VI or a stereoisomer, salt, tautomer or N-oxide thereof

the step of converting by reacting with
(wherein R ¹ is as defined in Appendix 12 or 13,
wherein R ² , R ³ , R ^N and X ¹ are as defined in Appendix 10 or 11)
15. The method of any one of clauses 12-14, further comprising:
(Appendix 16)
Dichloropyridazineamine compounds of formula IVa or salts, tautomers or N-oxides thereof

(wherein R ¹ is CH ₂ CH ₃ ),
or a dichloropyridazineamine compound of formula IVb or a salt, tautomer or N-oxide thereof

(wherein R ¹ is CH ₂ CH ₃ ).
(Appendix 17)
A mixture of a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof of Formula IVa as defined in Appendix 16 and a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof.

Claims (18)

Pyridazineamine compounds of formula V or salts, tautomers or N-oxides thereof

A method for manufacturing a
(a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c ) a mixture of (a) and (b)

and hydrogen in the presence of a hydrogenation catalyst
(In the formula,
^R1 is _{CH2CH3 )}
method including. 2. The method of claim 1, wherein the reaction is carried out in the absence of HCl scavenger. 3. A process according to claim 1 or 2, wherein the HCl scavenger is added after removal of the hydrogenation catalyst. 4. The method of claim 3, wherein said HCl scavenger is provided without water. HCl scavengers 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 Bases including metal 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 combinations thereof; buffers comprising sodium acetate and/or ammonium formate; precursors of ionic liquids comprising imidazole; and combinations thereof. the method of. 6. A process according to any one of claims 1 to 5, wherein the hydrogenation catalyst is selected from the group consisting of platinum or palladium on a support, Raney nickel and Raney cobalt. 7. A process according to any one of claims 1 to 6, wherein the hydrogenation catalyst is platinum or palladium on carbon. (a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c ) a mixture of (a) and (b)

of,
Formula III

by reacting a trichloropyridazine compound with an amine compound R ¹ —NH ₂ or a salt thereof
(wherein ^R1 is as defined in claim 1)
further comprising
Optionally, formula III

the trichloropyridazine compound of
Formula II

by reacting a compound of with _POCl3 ,
8. A method according to any one of claims 1-7. Formula II

a compound of
Mucochloric acid (I)

9. The method of claim 8, further comprising the step of reacting with hydrazine or a salt thereof. A pyridazine amine compound of formula V or a salt, tautomer or N-oxide thereof, a compound of formula VII or a stereoisomer, salt, tautomer or N-oxide thereof

to the
Pyridazineamine compounds of formula V or salts, tautomers or N-oxides thereof

and a compound of formula VI or a stereoisomer, salt, tautomer or N-oxide thereof

the step of converting by reacting with
(where R ¹ is as defined in claim 1,
R ² is H, halogen, CN, NO ₂ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl, or C ₂ -C ₁₀ -alkynyl, wherein the last three The group may be unsubstituted, partially or fully halogenated, or have 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, wherein the last five mentioned groups may be unsubstituted or R ^y and optionally having 1, 2, 3, 4 or 5 identical or different substituents selected from R ^x groups,
R ³ is H, halogen, CN, NO ₂ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl or C ₂ -C ₁₀ -alkynyl, the last three groups mentioned being non- may be substituted, may be partially or fully halogenated, or may have 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 and the last five mentioned groups may be unsubstituted or R ^y and R ^x groups may have 1, 2, 3, 4 or 5 identical or different substituents selected from
R ^N is H, CN, NO ₂ , C ₁ -C ₁₀ -alkyl, C ₂ -C ₁₀ -alkenyl or C ₂ -C ₁₀ -alkynyl, the last three groups mentioned being unsubstituted may be present, may be partially or fully halogenated, or may have 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, C3 _- C10 _- cycloalkyl, C3 _- C10 _- cycloalkenyl, heterocyclyl-C1 _- C5 _- alkyl, hetaryl-C1 _- C5 _- alkyl, C3 _- C10 _- cyclo alkyl-C ₁ -C ₅ -alkyl, C ₃ -C ₁₀ -cycloalkenyl-C ₁ -C ₅ -alkyl, phenyl-C ₁ -C ₅ -alkyl or phenyl and the last 10 groups ring may be unsubstituted or may have 1, 2, 3, 4 or 5 identical or different substituents R ^y ,
R ^a , R ^b , R ^c are independently of each other H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkyl methyl, C3-C6-halocycloalkyl, _{C2 - C4 -} alkenyl, _C2 -C4-haloalkenyl, _C2 - _{C4 -} alkynyl, C1- _{C4 -} alkoxy-C1 _{- C4} -alkyl, heterocyclyl, heterocyclyl-C ₁ -C ₄ -alkyl, phenyl, hetaryl, phenyl-C ₁ -C ₄ -alkyl and hetaryl-C ₁ -C ₄ -alkyl, wherein the last-mentioned 6 The rings in each group may be unsubstituted or independently of each other 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, wherein R ^d is C ₁ -C ₄ -alkyl, C1 _{- C4 -} haloalkyl, C3-C6 _- cycloalkyl, C3-C6-cycloalkylmethyl, C3-C6 _{- halocycloalkyl} , _{C2 - C4 -} alkenyl, _C2 - _C4 -haloalkenyl, _C2 - _{C4 -} alkynyl, C1- _C4 -alkoxy-C1 _{- C4} -alkyl, heterocyclyl, heterocyclyl-C1 _{- C4} -alkyl, phenyl, hetaryl, phenyl-C1 _- C4-alkyl The rings in the last 6 groups selected from ₄ -alkyl and hetaryl-C ₁ -C ₄ -alkyl may be unsubstituted or independently of each other halogen, CN, NO ₂ , C ₁ , 2, 3, 4 or 5 selected from ₁ - _C4 -alkyl, C1- _{C4 -} haloalkyl, C1- _C4 -alkoxy and C1- _{C4 -} haloalkoxy; may have a substituent,
R ^e , R ^f are independently of each other H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkylmethyl, C ₃ -C6- _{halocycloalkyl} , _C2 - _C4 -alkenyl, _C2 -C4-haloalkenyl, _C2 - _{C4 -} alkynyl, C1- _C4 -alkoxy-C1 _{- C4 -} alkyl, C1- _{C4 -} alkylcarbonyl, C1- _{C4 -} haloalkylcarbonyl, C1- _{C4 -} alkylsulfonyl, C1- _{C4 -} haloalkylsulfonyl, heterocyclyl, heterocyclyl-C1 _{- C4} -alkyl, heterocyclylcarbonyl , heterocyclylsulfonyl, phenyl, phenylcarbonyl, phenylsulfonyl, hetaryl, hetarylcarbonyl, hetarylsulfonyl, phenyl-C ₁ -C ₄ -alkyl and hetaryl-C ₁ -C ₄ -alkyl, the last-mentioned 12 The rings in each group may be unsubstituted or independently of each other halogen, CN, NO ₂ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ - may have 1, 2, 3, 4 or 5 substituents selected from alkoxy and C ₁ -C ₄ -haloalkoxy, or
R ^e and R ^f , together with the nitrogen atom to which they are attached, are 5- or 6-membered saturated or unsaturated groups optionally having a further heteroatom selected from O, S and N as ring member atoms. Forming a saturated heterocyclic ring, the heterocyclic ring may be unsubstituted or independently of one another halogen, CN, NO ₂ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ optionally has 1, 2, 3, ₄ or 5 substituents selected from -C4-alkoxy and C1- _{C4 -} haloalkoxy,
R ^g , R ^h are independently of each other H, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -halocycloalkyl, C ₂ - _C4 -alkenyl, _C2 -C4-haloalkenyl, _C2 - _{C4 -} alkynyl, C1- _C4 -alkoxy-C1 _{- C4 -} alkyl, heterocyclyl, heterocyclyl-C1 _{- C4-} the rings in the last-mentioned six groups may be unsubstituted or selected from alkyl, phenyl, hetaryl, phenyl-C ₁ -C ₄ -alkyl and hetaryl-C ₁ -C ₄ -alkyl; one selected independently from each other from halogen, CN, NO2, C1 _{- C4 -} alkyl, C1- _{C4 -} haloalkyl, C1- _{C4 -} alkoxy and C1- _{C4 -} haloalkoxy, optionally having 2, 3, 4 or 5 substituents,
R ⁱ is 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 ₁ -C The phenyl rings in the last two mentioned groups, selected from ₄ -alkyl, may be unsubstituted or independently of _each other halogen, CN, NO2, C1 _{- C4 -} alkyl, C1 It may have 1, 2, 3, ₄ or 5 substituents selected from -C4-haloalkyl, C1- _{C4 -} alkoxy and C1- _{C4 -} haloalkoxy. ,
^Rx is CN, NO2, C1 _{- C4 -} alkoxy, C1 _{- C4 -} haloalkoxy, S(O) _mRd , S ⁽ O ^{) mNReRf} , C1 _{- C10-} alkylcarbonyl, C1- _{C4 -} haloalkylcarbonyl, C1- _{C4 -} alkoxycarbonyl, C1 _{- C4 - haloalkoxycarbonyl} , C3-C6-cycloalkyl, 5- to 7-membered heterocyclyl, 5-membered or 6-membered hetaryl, phenyl, C3-C6-cycloalkoxy, _3- to ₆ -membered heterocyclyloxy, and phenoxy, wherein the last seven named groups are unsubstituted or may have 1, 2, 3, 4 or 5 R ^y groups,
R ^y is 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 , C ₁ -C ₄ -alkylcarbonyl, C ₁ -C ₄ -haloalkylcarbonyl, C ₁ -C ₄ -alkoxycarbonyl, C ₁ -C ₄ -haloalkoxycarbonyl, C ₃ -C6-cycloalkyl, C3-C6- _{halocycloalkyl} , _{C2 - C4 -} alkenyl, _C2 - _C4 -haloalkenyl, _C2 - _{C4 -} alkynyl and C1- _C4 -alkoxy - is selected from -C1 _{- C4} -alkyl;
Y is O or S,
m is 0, 1 or 2;
X ¹ is a leaving group)
10. The method of any one of claims 1-9, further comprising 11. The method of claim ¹⁰ , wherein X1 is selected from halogen, N3, p _- nitrophenoxy and pentafluorophenoxy. R ¹ is CH ₂ CH ₃ and
R ² is C ₁ -C ₄ -alkyl which may be unsubstituted or partially or fully halogenated,
R3 is H ^,
RN is a -CR ^{4 R 5} R ⁶ group,
R ⁴ is C 1 -C 4 ^-alkyl (C ₁ -C ₄ -alkyl ( R ^x is selected from CN and C(O)NH ₂ ⁾ and C ₃ to C6 _- cycloalkyl ( ^Ry is selected from halogen, CN and C(O) _NH2 );
R ⁵ is C 1 -C 4 ^-alkyl (C ₁ -C ₄ -alkyl ( R ^x is selected from CN and C(O)NH ₂ ) and C ₃ which may be unsubstituted or may have 1, 2 or 3 identical or different substituents R ^y _-C6 -cycloalkyl ( ^Ry is selected from halogen, CN and C(O) _NH2 );
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 carbocyclic ring optionally partially or fully substituted with R ^j , wherein , R ^j are selected from halogen, CN and C(O)NH ₂ ;
^R6 is H,
X ¹ is a leaving group,
11. The method of claim 10. 13. The method of claim ¹² , wherein X1 is selected from halogen, N3, p _- nitrophenoxy and pentafluorophenoxy. (a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c ) a mixture of (a) and (b)

A method for manufacturing a
Formula III

with an amine compound R1 ^- _NH2 or a salt thereof _, wherein ^R1 is _CH2CH3 .
including
Optionally, formula III

the trichloropyridazine compound of
Formula II

with _POCl3 . Formula II

a compound of
Mucochloric acid (I)

15. The method of claim 14, further comprising the step of reacting with hydrazine or a salt thereof. (a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c ) a mixture of (a) and (b) to form a pyridazineamine compound of Formula V or a salt, tautomer or N-oxide thereof;

to the
(a) a dichloropyridazineamine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazineamine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c ) a mixture of (a) and (b)

and hydrogen by reacting in the presence of a hydrogenation catalyst
(wherein R ¹ is as defined in claim 10)
further comprising
Optionally, the pyridazine amine compound of Formula V or a salt, tautomer or N-oxide thereof is combined with a compound of Formula VII or a stereoisomer, salt, tautomer or N-oxide thereof.

to the
Pyridazineamine compounds of formula V or salts, tautomers or N-oxides thereof

and a compound of formula VI or a stereoisomer, salt, tautomer or N-oxide thereof

the step of converting by reacting with
(wherein R ¹ is as defined in claim 10,
wherein ^R2 , R3 ^{, RN} and X1 are as defined in any ^one of claims 10-13 )
16. The method of claim 14 or 15, further comprising Dichloropyridazineamine compounds of formula IVa or salts, tautomers or N-oxides thereof

(wherein ^R1 is _CH2CH3 ) _,
or a dichloropyridazineamine compound of formula IVb or a salt, tautomer or N-oxide thereof

(wherein R ¹ is CH ₂ CH ₃ ). 18. A mixture of a dichloropyridazineamine compound of formula IVa or a salt, tautomer or N-oxide thereof and a dichloropyridazineamine compound of formula IVb or a salt, tautomer or N-oxide thereof as defined in claim 17.