process for preparing a compound

专利摘要:
The present invention relates to a process for the preparation of a Formula V pyridazine amine compound and to the processes for the preparation of Formula IVa, IVb, dichloropyridazine amine compounds or mixtures thereof. In addition, the present invention relates to the innovative dichloropyridazine amine compounds of Formula IVa, IVb, or mixtures thereof, wherein the amino group is an ethylamino group.
公开号:BR112017023935B1
申请号:R112017023935-3
申请日:2016-05-10
公开日:2020-07-07
发明作者:Eric George Klauber；Michael Rack；Roland Goetz；Sebastian Sõrgel
申请人:Basf Se；
IPC主号:

专利说明:

FIELD OF THE INVENTION
[0001] The present invention relates to a process for the preparation of a Formula V pyridazine amine compound, according to the following reaction sequence:
BRIEF DESCRIPTION OF THE INVENTION
[0002] In the scheme above and in the following, step (i) represents the conversion of mucochloric acid I to a Formula II compound, step (ii) represents the conversion of a Formula II compound to the Formula III trichloropyridazine compound , step (iii) represents the conversion of the trichloropyridazine compound of Formula III to a mixture of the dichloropyridazine amine compounds of Formulas IVa and IVb, and step (iv) represents the conversion of the mixture of the compounds of Formulas IVa and IVb into pyridazine compound of Formula V. It is emphasized that steps (ii) and (iii) can also be carried out through a single vessel reaction, 0 which is indicated with reference to steps (ii) + (iii) in the above scheme.
[0003] The pyridazine amine compounds obtained from Formula V can be reacted with the Formula VI compounds to provide the Formula VII compounds according to the following reaction scheme
[0004] Next, this reaction step is referred to as step (v).
[0005] Pyridazine amine compounds, in particular pyridazine amine compounds with an amino group at position 4 of the pyridazine moiety, are the versatile intermediate compounds for the preparation of pyridazine-derived fine chemicals, such as compounds in the pharmaceutical and agrochemical field. For example, pyridazine amine compounds are the focus of pharmaceutical research, which, for example, are suitable for the treatment of Alzheimer's dementia, depression, hypotension and anxiety. In addition, pyridazine amine compounds are versatile intermediate compounds for the preparation of pesticides with a portion of pyridazine, such as 4-pyrazol-N-pyridazinamide compounds, which are known to be especially useful in combating pests of invertebrates (see publications WO 2009/027393, WO 2010/034737, WO 2010/034738 and WO 2010/112177).
[0006] For certain applications, pyridazine amine compounds are desired, which do not comprise any other substituent regardless of the amino substituent, especially pyridazine amine compounds, which are not yet substituted by halogen substituents, for example , chlorine. However, chlorine substituents are often present in pyridazine amine compounds, as the typical starting material for the preparation of these compounds by means of a nucleophilic substitution reaction with an amine compound which is 3,4,5- trichloropyridazine.
[0007] In view of the above, an effective dehalogenation process is necessary, in which the dichloropyridazine amine compounds can be converted to pyridazine amine compounds. In particular, a process is needed, which provides improved yields. In view of further transformations of the resulting pyridazine amines, it is still desired to carry out the reaction without the addition of water.
[0008] It is known in the state of the art that the dehalogenation of certain dichloropyridazine amine compounds can be carried out through a hydrogenation / dehalogenation reaction in the presence of hydrogen and a hydrogenation catalyst. The state of the art suggests that this hydrogenation / dehalogenation of pyridazine amine compounds is carried out in the presence of a base. In this regard, reference is made to publications WO 2011/038572; Journal of Heterocyclic Chemistry, 21 (5), 1,389-92; 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, publication WO 2011/038572 describes the dehalogenation of a mixture of 3,5-dichloro-4-pyridazinamine and 5,6-dichloro-4-pyridazinamine by reacting the mixture with hydrogen in the presence of a hydrogenation catalyst (Pd / C) and a base (sodium hydroxide).
[0009] The reason the base is added is to avoid catalyst poisoning due to the production of HCI in the reaction. This is explained by F. Chang et al. in Bull. Korean Chem. Soc. 2011, 32 (3), 1.075, an article that refers to Pd-catalyzed dehalogenations of aromatic halides. It has been reported that HCI produced from dechlorination tends to be absorbed into the activated carbon, leading to progressive Pd / C intoxication, and that it is efficient to add some bases for HCI removal. It is also described that conversions in the dechlorination reaction can be increased in the presence of a base.
[0010] However, the addition of a base is disadvantageous, especially for an industrially applicable process. First, an additional chemical substance is required for the reaction, ie the base, which makes the process more complex. Second, the presence of the base makes it difficult to recycle the catalyst. In particular, when removing the hydrogenation catalyst by filtration after the reaction, the chloride salts obtained from the reaction of the base with the HCI will additionally be removed through filtration, so that the filter cake comprises the catalyst and the chloride salt (for example, KCI and KHCO3). Another processing procedure is then necessary to re-isolate the catalyst.
[0011] It is therefore an object of the present invention to provide a process for the dehalogenation of dichloropyridazine amine compounds, which is suitable for industrial application.
[0012] In particular, it is an object of the present invention to provide a process, which does not require the addition of a base as an additional chemical, and which provides the advantage that the hydrogenation catalyst can be recycled after the reaction without purification. At the same time, it is clear that you want to provide high process yields.
[0013] The above object is achieved through process A, as described below, and in independent Claim 1 and in Claims that depend directly or indirectly on it. DETAILED DESCRIPTION OF THE INVENTION
[0014] In a first aspect, the present invention, therefore, relates to a process, which is hereinafter referred to as process A, for the preparation of a Formula V pyridazine amine compound or a salt, tautomer or N-oxide
which comprises the reaction step of (a) a Formula IVa dichloropyridazine amine compound or a salt, tautomer or N-oxide thereof, or (b) a Formula IVb dichloropyridazine amine compound or a salt, tautomer or N -oxide, or (c) a mixture of (a) and (b)
with hydrogen in the presence of a hydrogenation catalyst, in which R1 is H, C1-C2 alkyl or C1-C2 alkoxy-C1-C2 alkyl.
[0015] Note that the reaction step underlying process A corresponds to step (iv) in the above reaction sequence.
[0016] Surprisingly it has been discovered by the Depositors of the present invention that the dehalogenation of dichloropyridazine amine compounds can be carried out in the absence of an HCI scavenger, that is, in the absence of a base or other chemical suitable for binding of HCI, and that the desired product, however, can be obtained in high yields. The hydrogenation catalyst can simply be removed by filtration after the reaction and can be recycled without purification.
[0017] It has also been discovered that an HCI scavenger, advantageously, can be used after removal of the hydrogenation catalyst, so that the hydrogen chloride is bound and will not be released in gaseous form.
[0018] When an HCI scavenger is used after removal of the hydrogenation catalyst, it has been found to be advantageous if the HCI scavenger is supplied without water, as this facilitates processing.
[0019] Furthermore, the Depositors of the present invention have surprisingly discovered that the yields of the dehalogenation of dichloropyridazine amine compounds depend on the nature of the amino substituent. In this context, it was surprisingly discovered that the reaction can advantageously be carried out with the dichloropyridazine amine compounds, where the amino group is an ethylamino group.
[0020] Dichloropyridazine amine compounds are also versatile intermediate compounds for the preparation of fine chemicals derived from pyridazine, such as compounds in the pharmaceutical and agrochemical fields. In particular, chlorine substituents enable additional derivations of the pyridazine moiety, for example, the introduction of additional amino groups through a nucleophilic substitution reaction. Consequently, a wide variety of compounds are available from dichloropyridazine amine compounds, since not only the amine group can react, for example, with an activated carboxylic acid derivative, but also chlorine substituents can be substituted by other substituents.
Consequently, there is also a need for an effective process for the preparation of dichloropyridazine amine compounds.
[0022] Furthermore, there is a need to supply dichloropyridazine amine compounds, where the amino group is an ethylamino group, since these compounds or their mixtures are of special interest as intermediates in the preparation of pesticides and products pharmacists.
[0023] Normally, dichloropyridazine amine compounds are prepared from 3,4,5-trichloropyridazine by means of a nucleophilic substitution reaction with an amine compound.
[0024] For example, publication WO 2011/038572 describes the preparation of a mixture of 3,5-dichloro-4-pyridazinamine and 5,6-dichloro-4-pyridazinamine by reacting 3,4,5-trichloropyridazine with ammonia gas for a reaction time of 4 days. The same reaction is also described in US patent 4,728,355, in which the reaction is carried out in a sealed tube at a temperature of 120 to 130 ° C for five days. The reaction is carried out at 125 ° C for 5 hours, according to Tsukasa Kuraishi et al. {Journal of Heterocyclic Chemistry, 1964, Vol. 1, pages 42-47).
[0025] The reaction conditions described above for this reaction indicate that the technique suggests that long reaction times or high temperatures are required for the nucleophilic substitution reaction, both of which are disadvantageous for commercial processes.
[0026] Furthermore, the preparation of dichloropyridazine amine compounds by reacting 3,4,5-trichloropyridazine with an amine compound, which is different from ammonia, appears to be accompanied by other problems.
[0027] Publication WO 1999/64402 describes the reaction of 3,4,5-trichloropyridazine with 3-amino-1-propanol as the nucleophile. Although the reaction is carried out in boiling ethanol, the yields are much lower (only 47.7% of the crude product), and laborious processing by means of crystallization is necessary to isolate the desired reaction products.
[0028] WO 2012/098387 describes the reaction of 3,4,5-trichloropyridazine with 2-methylamino-ethanol as the nucleophile. Although a secondary amine, which is more nucleophilic than a primary amine, is used as a nucleophile, the reaction is not quantitative and laborious processing using column chromatography is required.
[0029] Donna L. Romero et al. (Journal of Medicinal Chemistry, 1996, Volume 39, No. 19, pages 3,769-3,789) describe the reaction of 3,4,5-trichloropyridazine with isopropylamine as a nucleophile. According to the information provided in the article, the reaction must be carried out at the reflux of toluene, that is, at a temperature of about 110 ° C. In addition, chromatography is necessary for purification.
Similarly, publication WO 1996/18628 describes the same reaction, in which 3,4,5-trichloropyridazine and isopropylamine are refluxed in toluene for three hours. Column chromatography is then required to isolate the desired 4-isopropylamino-3,5-dichloropyridazine compound.
[0031] Therefore, processes for the preparation of dichloropyridazine amines, as described in the prior art, are disadvantageous in terms of reaction conditions, yields and / or processing requirements.
[0032] Furthermore, it is another disadvantage of the processes described in the prior art that the irritating 3,4,5-trichloropyridazine compound must be prepared and handled as a starting material. The solid handling of 3,4,5-trichloropyridazine is especially disadvantageous on a commercial scale.
[0033] It is therefore an object of the present invention to provide a process for the preparation of dichloropyridazine amine compounds, which overcomes the disadvantages in terms of reaction conditions, yields and / or processing requirements, as is evident from the from the prior art, or the disadvantage in terms of the use of the irritating 3,4,5-trichloropyridazine as starting material.
[0034] In this context, it is of special interest to provide a direct process, which is suitable for escalation and provides satisfactory yields, preferably yields greater than 90%.
[0035] The above object is achieved through process B, as described below and in independent Claim 12 and in Claims that depend directly or indirectly on it.
[0036] In a second aspect, the present invention therefore relates to a process, which hereinafter is referred to as process B, for the preparation of (a) a Formula IVa dichloropyridazine amine compound or a salt thereof , tautomer or N-oxide, or (b) a dichloropyridazine amine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c) a mixture of (a) and (b)
in a single vessel reaction comprising the steps reacting a compound of Formula II
with POCI3, and the reaction of the resulting crude reaction product with an amine compound R1-NH2 or a salt thereof, wherein R1 is H, C1-C2 alkyl or C1-C2 alkoxy-C1-C2 alkoxy.
[0037] It was observed that the single vessel reaction underlying process B corresponds to steps (ii) + (iii) in the above reaction sequence.
[0038] Surprisingly, it was discovered that the process of preparing dichloropyridazine amine compounds should not necessarily be started from 3,4,5-trichloropyridazine. Instead, 3,4,5-trichloropyridazine can be prepared in situ in a single vessel reaction with a compound of Formula II as a starting material. The 3,4,5-trichloropyridazine formed in situ then is directly reacted with the amine compound to provide the desired dichloropyridazine amine compounds.
[0039] This process is particularly advantageous for safety reasons, since it is not necessary to isolate and manipulate the irritating 3,4,5-trichloropyridazine compound. This makes the process more favorable for industrial applications. In addition, the process is more economical and suitable for scaling.
[0040] Furthermore, it has been discovered that the very high yields of the dichloropyridazine amine compounds can be obtained through the above process, in which the reaction of the 3,4,5-trichloropyridazine formed in situ with the amine compound does not require rigorous reaction. Due to the high yields, laborious processing can also be avoided.
[0041] The above object is also achieved through process C as described below and in independent Claim 13 and in Claims that directly or indirectly depend on it.
[0042] In a third aspect, the present invention therefore relates to a process, which hereinafter is referred to as process C, for the preparation of (a) a Formula IVa dichloropyridazine amine compound or a salt thereof , tautomer or N-oxide, or (b) a dichloropyridazine amine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c) a mixture of (a) and (b)
which comprises the reaction step of a Formula III trichloropyridazine compound
with an amine compound R1-NH2 or a salt thereof, where R1 is CH2CH3, and where the process optionally still comprises the step of preparing the Formula III trichloropyridazine compound
through the reaction of a Formula II compound
with POCI3.
[0043] It is observed that the reaction step of the underlying process C is covered by step (iii) in the above reaction sequence. Optionally, step (ii) of the above reaction sequence is also carried out.
[0044] Surprisingly, it has been found that the process of preparing dichloropyridazine amine compounds is especially advantageous if ethylamine is used as a nucleophile in the nucleophilic substitution reaction. Although the prior art suggests stringent reaction conditions or at least very long reaction times for the nucleophilic substitution reaction, the Depositors of the present invention have found that the reaction conditions moderate with the reaction temperatures, for example, not exceeding 100 ° C and reaction times of no more than 12 hours are sufficient to supply the desired dichloropyridazine ethylamines in high yields and without laborious processing.
[0045] In a fourth aspect, the present invention relates to the Formula IVa dichloropyridazine amine compound or a salt, tautomer or N-oxide thereof;
wherein R1 is CH2CH3; or a dichloropyridazine amine compound of Formula IVb or a salt, tautomer or N-oxide thereof,
where R1 is CH2CH3.
[0046] Furthermore, the present invention relates to a mixture of the Formula IVa dichloropyridazine amine compound or a salt, tautomer or N-oxide thereof and the Formula IVb dichloropyridazine amine compound or a salt, tautomer or N -oxide as defined above.
[0047] As indicated above, these compounds are highly versatile precursors for the preparation of chemicals, such as compounds in the pharmaceutical and agrochemical field. Also, advantageously, they can be used in the hydrogenation / dehalogenation process, as described herein.
[0048] In a fifth aspect, the present invention relates to a process for the preparation of a compound of Formula VII * or a stereoisomer, salt, tautomer or N-oxide
comprising the reaction step of a Formula V pyridazine amine compound or a salt, tautomer or N-oxide thereof
with a compound of Formula VI * or a stereoisomer, salt, tautomer or N-oxide
wherein R1 is CH2CH3; and wherein R2 is CH3, R3 is H, R4 is CH3, R5 is CH3 and R5 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 OH, 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, they are CH2CH2CF2CH2CH2 and R6 is H; and where X1 is an leaving group which is preferably selected from halogen, N3, p-nitrophenoxy and pentafluorophenoxy and especially preferably, is chlorine.
[0049] The following process is referred to as process D. It was observed that the reaction step underlying process D is covered by step (v) in the above reaction sequence.
[0050] The process illustrates that the pyridazine amine compounds, which can be obtained through the hydrogenation / dehalogenation process, as described herein, are important intermediates in the preparation of 4-pyrazol-N-pyridazinamide compounds, which are pesticides , for example, suitable for invertebrate pest control.
[0051] It should be understood that processes A, B, C and D, as defined above, can optionally still comprise the additional reaction steps of the reaction sequence provided above.
[0052] For example, process A can optionally still comprise step (iii) and optionally also step (ii), in which steps (ii) and (iii) can be performed separately or together with steps (ii) + (iii) in the single vessel reaction. In addition, process A may optionally still comprise step (i). In addition, it should be understood that process A, optionally, can still comprise step (v).
[0053] Process B, optionally, can still comprise step (i) and / or step (iv). In addition, step (v) can optionally follow after step (iv).
[0054] Process C, optionally, can still comprise step (i) and / or step (iv). In addition, step (v) can optionally follow after step (iv).
[0055] Process D, optionally, can still comprise one or more of the previous steps (iv), (iii), (ii) or (i), as indicated in the reaction sequence above.
[0056] It should be understood that the reaction steps of the reaction sequences indicated above, which are preferably covered by processes A, B, C or D, can be carried out separately, that is, under isolation of the intermediate compounds, or without the isolation of the intermediate compounds. In particular, it is preferable that certain subsequent steps are carried out in one-step reactions, for example, in the case of steps (ii) + (iii).
[0057] Furthermore, it is emphasized that the reaction steps can be carried out on a technical scale. Preferably, the reagents are converted equally well and only minor deviations in terms of yield are observed.
[0058] In the context of the above aspects of the present invention, the following definitions are provided.
[0059] The "compounds of the present invention" or "compounds according to the present invention", that is, the compounds of Formulas I, II, III, IVa, IVb, V, VI and VII (as well as VI * and VII *), as defined herein, comprise the compound (s) such as their salts, tautomers or N-oxides, if formation of these derivatives is possible; and, if there are chirality centers, which may especially be the case for compounds VI and VII, as well as compounds VI * and VII *, also their stereoisomers.
[0060] As used herein, the term "pyridazine amine compound (s)" refers to compounds of Formula V, that is, pyridazine compounds with an amino group -NHR1 as a substituent at position 4 of the pyridazine moiety . Therefore, the pyridazine amine compounds according to the present invention do not comprise any other substituent on the pyridazine ring.
[0061] As used herein, the term "dichloropyridazine amine compound (s)" encompasses compounds of Formula IVa or IVb or their combination, that is, pyridazine compounds with an amino group - NHR1 as a substituent and two chlorine substituents, where the substituents are present at the positions of the pyridazine moiety, which can be derived from Formulas IVa and IVb.
[0062] As used herein, the term "trichloropyridazine amine compound (s)" preferably refers to compounds of Formula III, that is, 3,4,5-trichloropyridazine.
[0063] Depending on the acidity or basicity, as well as the reaction conditions, the compounds of the present invention may be present in the form of salts. Such salts will normally be obtained by reacting the compound with an acid, if the compound has a basic functionality, such as an amine, or by reacting the compounds with a base, if the compound has an acidic functionality, such as an acid group carboxylic.
[0064] The cations, which are derived from a base, with which the compounds of the present invention are reacted, for example, are the alkali metal cations Ma +, the alkaline earth metal cations Mea2 + or the ammonium cations NR4 +, where the alkali metals are preferably sodium, potassium or lithium and the alkaline earth metal cations are preferably magnesium or calcium and where the R4 substituents of the ammonium cation NR4 +, preferably independently, are selected from H, C-C10 alkyl, phenyl and phenyl-C1-C2 alkyl. Suitable cations, in particular, are alkali metal ions, preferably lithium, sodium and potassium, alkaline earth metals, preferably calcium, magnesium and barium, and transition metals, preferably manganese , copper, zinc and iron, and also ammonium (NH4 +) and substituted ammonium where one to four of the hydrogen atoms are replaced by C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C-C4-alkyl alkoxy C1-C4, C1-C4 hydroxyalkoxy-C1-C4 alkyl, phenyl or benzyl. Examples of substituted ammonium ions include methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trimethylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxyethylammonium, 2- (2-hydroxy-ethoxy) ethylammonium, bis (2-hydroxyethyl) benzyltriethylammonium, in addition, phosphonium ions, sulfonium ions, preferably tri (C 1 -C 4 alkyl) sulfonium and sulfoxonium ions, preferably tri (C 1 -C 4 alkyl) sulfoxonium.
[0065] The anions, which are derived from an acid, with which the compounds of the present invention have been reacted, for example, are chloride, bromide, fluoride, hydrogensulfate, sulfate, dihydrogen phosphate, hydrogen phosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate and anions of C1-C4 alkanoic acids, preferably the format, acetate, propionate and butyrate.
[0066] Tautomers of the compounds of the present invention include keto-enol tautomers, imine-enamine tautomers, amide-imidic acid tautomers and the like. The compounds of the present invention comprise all possible tautomers.
[0067] The term "N-oxide" refers to a form of the compounds of the present invention in which at least one nitrogen atom is present in the oxidized form (such as NO). The N-oxides of the compounds of the present invention can only be obtained if the compounds contain a nitrogen atom, which can be oxidized. N-oxides can mainly be prepared using conventional methods, for example, using the method described in Journal of Organometallic Chemistry1989, 370, 17-31. However, preferably, according to the present invention, it is that the compounds are not present in the form of N-oxides. On the other hand, under certain reaction conditions, it cannot be prevented that N-oxides are formed, at least, as intermediates.
[0068] The term "stereoisomers" encompasses both optical isomers, such as enantiomers or diastereomers, the latter existing due to more than one chirality center in the molecule, as well as geometric isomers (cis / trans isomers). Depending on the pattern of substitution, the compounds of the present invention may have one or more chirality centers, in which case they may be present as mixtures of enantiomers or diastereomers. The present invention provides the pure enantiomers or diastereomers and mixtures thereof. Suitable compounds of the present invention also include all possible geometric stereoisomers (cis / trans isomers) and mixtures thereof.
[0069] The compounds of the present invention can be in the form of solids or liquids or in gaseous form. If the compounds are present as solids, they may be amorphous or they may exist in one or more different crystalline states (polymorphs) that may have different macroscopic properties, such as stability or have different biological properties, such as activities. The present invention includes amorphous or crystalline compounds, mixtures of different crystalline states, as well as their amorphous or crystalline salts.
[0070] The organic portions mentioned in the definitions above the variables are - like the term halogen - collective terms for the individual lists of the individual members of the group. The Cn-Cm prefix, in each case, indicates the possible number of carbon atoms in the group.
[0071] The term "halogen", in each case, means fluorine, bromine, chlorine or iodine, in particular, fluorine, chlorine or bromine.
[0072] The term "alkyl" as used herein and in the alkyl portions of alkylamino, alkylcarbonyl, alkylthio, alkylsulfenyl, alkylsulfonyl and alkoxyalkyl, in each case, indicates a straight or branched chain alkyl group, normally containing from 1 to 10 carbon atoms, often from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, and in particular from 1 to 3 carbon atoms. Examples of an alkyl group 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-dibutylmethyl, 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.
[0073] The term “haloalkyl”, as used in the present and haloalkyl moieties of haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylthio, haloalkylsulfonyl, haloalkylsulfinyl, haloalkoxy and haloalkoxyalkyl, in each case, indicates a linear group or a group of linearly indicated or a linear group 1 to 10 carbon atoms, often from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, where the hydrogen atoms in this group are partially or completely replaced by halogen atoms. The haloalkyl moieties are preferably selected from C1-C4 haloalkyl, more preferably from C1-C3 haloalkyl or C1-C2 haloalkyl, in particular from C1-2 fluoralkyl, such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and the like.
[0074] The term "alkoxy" as used herein, in each case, indicates a straight or branched chain alkyl group that is bonded by means of an oxygen atom and normally contains 1 to 10 carbon atoms, often of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples of an alkoxy group are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert-butyloxy and the like.
[0075] The term "alkoxyalkyl", as used herein, refers to alkyl which in general comprises 1 to 10, often 1 to 4, preferably 1 to 2 carbon atoms, where 1 atom of carbon carries an alkoxy radical that normally comprises 1 to 4, preferably 1 or 2 carbon atoms, as defined above. Examples are CH2OCH3, CH2-OC2H5, 2- (methoxy) ethyl, and 2- (ethoxy) ethyl.
[0076] The term "haloalkoxy", as used herein, in each case, indicates a straight or branched chain alkoxy group containing from 1 to 10 carbon atoms, often from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, in which the hydrogen atoms in this group are partially or totally replaced by halogen atoms, in particular, fluorine atoms. The haloalkoxy moieties preferably include the C1-C4 haloalkoxy, in particular the C1-C2 fluoroalkoxy, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2 difluoroethoxy, 2,2,2-trifluoro , 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoro-ethoxy, 2,2dichloro-2-fluorethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy and the like.
[0077] The term "alkylsulfonyl" (S-alkyl (= O) 2-), as used herein, refers to a straight or branched chain saturated alkyl group containing from 1 to 10 carbon atoms, preferably of 1 to 4 carbon atoms (= C1-C4 alkylsulfonyl), preferably 1 to 3 carbon atoms, which is linked via the sulfonyl atom of the sulfonyl group, at any position in the alkyl group.
[0078] The term "haloalkylsulfonyl", as used herein, refers to an alkylsulfonyl group, as mentioned above, in which the hydrogen atoms are partially or completely replaced by fluorine, chlorine, bromine and / or iodine.
[0079] The term "alkylcarbonyl" refers to an alkyl group as defined above, which is attached via the carbon atom of a carbonyl group (C = O) to the rest of the molecule.
[0080] The term "haloalkylcarbonyl" refers to an alkylcarbonyl group, as mentioned above, in which the hydrogen atoms are partially or completely replaced by fluorine, chlorine, bromine and / or iodine.
[0081] The term "alkoxycarbonyl" refers to an alkyl group as defined above, which is linked by means of an oxygen atom to the rest of the molecule.
[0082] The term "haloalkoxycarbonyl" refers to an alkoxycarbonyl group, as mentioned above, in which the hydrogen atoms are partially or completely replaced by fluorine, chlorine, bromine and / or iodine.
[0083] The term "alkenyl" as used herein, in each case, indicates an individually unsaturated hydrocarbon radical that normally contains 2 to 10, often 2 to 6, preferably 2 to 4 carbon atoms, for example, vinyl, allyl (2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, metallyl (2-methyl-prop-2-en-1-yl), 2-buten-1-yl, 3-buten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1 - useful, 2-ethylprop-2-en-1-yl and the like.
[0084] The term "haloalkenyl", as used herein, refers to an alkenyl group as defined above, in which the hydrogen atoms are partially or completely replaced by halogen atoms.
[0085] The term "alkynyl" as used herein, in each case, indicates an individually unsaturated hydrocarbon radical that typically contains 2 to 10, often 2 to 6, preferably 2 to 4 carbon atoms , for example, ethynyl, propargyl (2-propin-1-yl), 1-propyn-1-yl, 1-methyl-prop-2-in-1-yl), 2-butin-1-yl, 3 -butin-1-yl, 1-pentin-1-yl, 3-pentin-1-yl, 4-pentin-1-yl, 1-methylbut-2-in-1-yl, 1-ethylprop-2-in -1 -il and the like.
[0086] The term "haloalkynyl", as used herein, refers to an alkynyl group, as defined above, in which the hydrogen atoms are partially or completely replaced by halogen atoms.
[0087] The term "cycloalkyl", as used in the present and the cycloalkyl portions of cycloalkoxy and cycloalkylmethyl, in each case, indicates a cycloaliphatic monocyclic radical that normally contains 3 to 10 or 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloeptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0088] The term "halocycloalkyl", as used herein, and in the halocycloalkyl moieties of halocycloalkoxy and halocycloalkyl, in each case, means a cycloaliphatic monocyclic radical that normally contains 3 to 10 C atoms or 3 to 6 atoms of C, where at least one, for example, 1,2, 3, 4 or 5 of the hydrogen atoms, is replaced by halogen atoms, in particular fluorine or chlorine. Examples are 1- and 2- fluorocyclopropyl, 1,2-, 2,2- and 2,3-difluorocyclopropyl, 1,2,2-trifluorocyclopropyl, 2,2,3,3-tetrafluorocyclpropyl, 1- and 2- chlorocyclopropyl, 1,2-, 2,2- and 2,3- dichlorocyclopropyl, 1,2,2-trichlorocyclopropyl, 2,2,3,3-tetrachlorocyclopropyl, 1-, 2- and 3-fluorocyclopentyl, 1,2- , 2,2-, 2,3-, 3,3-, 3,4-, 2,5-difluorocyclopentyl, 1-, 2- and 3-chlorocyclopentyl, 1,2-, 2,2-, 2,3 -, 3,3-, 3,4-, 2,5-dichlorocyclopentyl and the like.
[0089] The term "cycloalkoxy" refers to a cycloalkyl group, as defined above, which is linked by means of an oxygen atom to the rest of the molecule.
[0090] The term "cycloalkylalkyl" refers to a cycloalkyl group, as defined above, which is attached by means of an alkyl group, such as a C1-C5 alkyl group or a C1-C4 alkyl group, in particular, a group methyl (= cycloalkylmethyl), to the rest of the molecule.
[0091] The term "cycloalkenyl", as used herein, and in the cycloalkenyl portions of cycloalkenyloxy and cycloalkenylthio, in each case, means an individually unsaturated monocyclic non-aromatic radical, usually containing 3 to 10, for example, 3 or 4 or from 5 to 10 carbon atoms, preferably from 3 to 8 carbon atoms. Examples of cycloalkenyl groups include cyclopropenyl, cycloeptenyl or cyclooctenyl.
[0092] The term "halocycloalkenyl", as used herein, and in the halocycloalkenyl moieties of halocycloalkenyloxy and halocycloalkenylthio, in each case, means an individually unsaturated, non-aromatic monocyclic radical, usually containing 3 to 10, for example, 3 or 4 or from 5 to 10 carbon atoms, preferably from 3 to 8 carbon atoms, where at least one, for example 1, 2, 3, 4 or 5 of the hydrogen atoms, are replaced by halogen, in particular, by fluorine or chlorine. Examples are 3,3-difluoro-cyclo-prop-1-yl and 3,3-dichlorocyclopropen-1-yl.
[0093] The term "cycloalkenylalkyl" refers to a cycloalkenyl group, as defined above, which is attached by means of an alkyl group, such as a C1-C5 alkyl group or a C1-C4 alkyl group, in particular, a group methyl (= cycloalkenylmethyl), to the rest of the molecule.
[0094] The term "carbocycle" or "carbocyclyl", in general, includes a monocyclic group with 3 to 12 members, preferably a non-aromatic monocyclic with 3 to 8 members or one with 5 to 8 members, more preferably, a group with 5 or 6 members, comprising from 3 to 12, preferably from 3 to 8 or 5 to 8, more preferably, from 5 or 6 carbon atoms. Preferably, the term "carbocycle" encompasses cycloalkyl and cycloalkenyl groups, as defined above.
[0095] The term "heterocycle" or "heterocyclyl", in general, includes heterocyclic, non-aromatic monocyclic radicals with 3 to 12 members, preferably with 3 to 8 members or with 5 to 8 members, most preferably with 5 or 6 members, in particular, with 6 members. Non-aromatic heterocyclic radicals usually comprise 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms selected from N, O and S as ring members, where S atoms as ring members may be present as S, SO or SO2. Examples of 5- or 6-membered heterocyclic radicals include saturated or unsaturated non-aromatic heterocyclic rings, such as oxiranyl, oxetanyl, tietanyl, tietanyl-S-oxide (S-oxothiietanyl), tietanyl-S-dioxide (S- dioxotietanil), pyrrolidinyl, pyrrolinyl, pyrazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, thiolanyl, S- oxothiolanila, S-dioxothiolanila, dihydrothienyl, S-oxodihydrothienyl, S- dioxodihydrothyl, pyridine, oxazolinin, oxazolidinyl, oxazolidin , pyranyl, dihydropyranyl, tetrahydropyranyl, 1,3- and 1,4-dioxanyl, thiopyranyl, S-oxothiopyranyl, S-dioxothiopyranyl, dihydrothiopyranyl, S-oxodihydrothiopyranyl, S-dioxodihydrothiopyranyl, tetrahydrothiopyranyl, oxymoranyl, Sodium thiomorpholinyl, S-oxothiomorpholinyl, S-dioxothiomorpholinyl, thiazinyl and the like. Examples of heterocyclic ring also comprise 1 or 2 carbonyl groups as ring members comprising pyrrolidin-2-onyl, pyrrolidin-2,5-dionyl, imidazolidin-2-onyl, oxazolidin-2-onyl, thiazolidin-2-onyl and the like.
[0096] The term "heteroaryl" includes the 5- or 6-membered monocyclic heteroaromatic radicals that comprise ring members 1, 2, 3 or 4 heteroatoms selected from N, O and S. Examples of heteroaromatic radicals with 5 or 6 members include pyridyl, i.e., 2-, 3-, or 4-pyridyl, pyrimidinyl, i.e., 2-, 4- or 5-pyrimidinyl, pyrazinyl, pyridazinyl, i.e., 3- or 4- pyridazinyl, thienyl, i.e., 2- or 3-thienyl, furila, 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, for example, 2- or 5- [1,3,4] oxadiazolyl, 4- or 5- (1,2,3-oxadiazole) useful, 3- or 5- (1,2,4-oxadiazole) useful, 2- or 5- (1,3 , 4-thiadiazole) yl, thiadiazolyl, for example, 2- or 5- (1,3,4-thiadiazole) useful, 4- or 5- (1,2,3-thiadiazole) useful, 3- or 5- (1,2,4-thiadiazole) useful, triazolyl, for example, 1H-, 2H- or 31-1-1 , 2,3 triazol-4-yl, 2H-triazol-3-yl, 1H-, 2H-, or 4H-1,2,4-triazolyl and tetrazolyl, i.e., 1H- or 2H-tetrazolyl. The term "heteroaryl" also includes 8 to 10-membered heteroaromatic bicyclic radicals that comprise ring members 1, 2 or 3 heteroatoms selected from N, O and S, in which a 5- or 6-membered heteroaromatic ring which is fused with a phenyl ring or a 5- or 6-membered heteroaromatic radical. Examples of a 5- or 6-membered heteroaromatic ring fused to a phenyl or 5- or 6-membered heteroaromatic radical include benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzoxazinyl, quinolinyl, quinoline purinyl, 1,8-naphthyridyl, pteridyl, pyrido [3,2-d] pyrimidyl or pyridoimidazolyl and the like. These fused hetaryl radicals can be attached to the remainder of the molecule via any 5- or 6-membered heteroaromatic ring atom or via a fused phenyl moiety carbon atom.
[0097] The term "aryl" includes aromatic mono-, bi- or tricyclic radicals normally containing 6 to 14, preferably 6, 10 or 14 carbon atoms. Examples of aryl groups include phenyl, naphthyl and anthracenyl . Phenyl is preferably an aryl group.
[0098] The terms "heterocyclyloxy", "heteroyloxy" and "phenoxy" refer to heterocyclyl, hetaryl and phenyl, which are linked by means of an oxygen atom to the rest of the molecule.
[0099] The terms "heterocyclylsulfonyl", "hetarylsulfonyl" and "phenylsulfonyl" refer to heterocyclyl, hetaryl and phenyl, respectively, which are linked by means of a sulfur atom of a sulfonyl group to the rest of the molecule.
[0100] The terms "heterocyclylcarbonyl", "hetarylcarbonyl" and "phenylcarbonyl" refer to heterocyclyl, hetaryl and phenyl, respectively, which are linked by means of a carbon atom of a carbonyl group (C = O) to the rest of the molecule .
[0101] The terms "heterocyclylalkyl" and "hetarylalkyl" refer to heterocyclyl or hetaryl, respectively, as defined above, which are linked via a C1-C5 alkyl group or a C1-C4 alkyl group, in particular a methyl group ( = heterocyclylmethyl or hetariolmethyl, respectively), to the rest of the molecule.
[0102] The term "phenylalkyl" refers to phenyl which is attached via a C1-C5 alkyl group or a C1-C4 alkyl group, in particular a methyl group (= arylmethyl or phenylmethyl), to the rest of the molecule, the examples including benzyl, 1-phenylethyl, 2-phenylethyl, and the like.
[0103] The term "alkylene" refers to alkyl, as defined above, which represents a linker between the molecule and a substituent.
[0104] Preferred embodiments in relation to processes A, B, C and D of the present invention are described below.
[0105] In general, the reaction steps carried out in processes A, B, C and D, as described in detail below, are carried out in usual reaction vessels for such reactions, the reactions being carried out continuously, semi-continuously or batchwise .
[0106] In general, special reactions will be carried out under atmospheric pressure. The reactions, however, can be carried out under reduced pressure.
[0107] The temperatures and duration of the reactions can be varied in wide intervals, which the technician in the subject knows of analogous reactions. The temperatures, in general, depend on the reflux temperature of the solvents. Other reactions, preferably, are carried out at room temperature, that is, at about 25 ° C, or under cooling with ice, that is, at about 0 ° C. The completion of the reaction can be monitored by the methods known by a technical subject, for example, thin layer chromatography or HPLC.
[0108] If not stated otherwise, the molar ratios of the reagents, which are used in the reactions, are in the range from 0.2: 1 to 1: 0.2, preferably from 0.5 : 1 to 1: 0.5, more preferably, from 0.8: 1 to 1: 0.8. Preferably, equimolar amounts are used.
[0109] If not indicated otherwise, the reagents, in principle, can be in contact with each other in any desired sequence.
[0110] The person skilled in the art knows when reagents or reagents are sensitive to moisture, so the reaction must be carried out under protective gases such as, for example, under a nitrogen atmosphere, and dry solvents must be used.
[0111] The person skilled in the art also knows the best processing of the reaction mixture after the end of the reaction.
[0112] In the following, the preferred embodiments are provided in relation to process A of the present invention. It is to be understood that the preferred embodiments mentioned above and those that are still illustrated below process A of the present invention are to be understood as preferably alone or in combination with each other.
[0113] As indicated above, the present invention relates, in a first aspect, to process A for the preparation of a Formula V pyridazine amine compound or a salt, tautomer or N-oxide thereof
which comprises the reaction step of (a) a dichloropyridazine amine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) a dichloropyridazine amine compound of Formula IVb or a salt, tautomer or N-oxide, or (c) a mixture of (a) and (b)
with hydrogen in the presence of a hydrogenation catalyst, in which R1 is H, C1-C2 alkyl or C1-C2 alkoxy-C1-C2 alkyl.
[0114] The reaction step underlying process A corresponds to step (iv) in the above reaction sequence.
[0115] The reaction step (iv) can only be carried out in the presence of a hydrogenation catalyst.
[0116] As used herein, the term "hydrogenation catalyst" encompasses heterogeneous and homogeneous hydrogenation catalysts, but preferably refers to heterogeneous catalysts. It is known in the prior art that platinum, palladium, rhodium and ruthenium form highly active catalysts. Non-precious metal catalysts, such as nickel-based catalysts (such as Raney nickel and Urushibara nickel) are economical alternatives. Preferably the hydrogenation catalysts according to the present invention are provided below.
[0117] As a secondary product of the reaction step (iv), hydrogen chloride is produced.
[0118] However, in a preferred embodiment of process A, the reaction is carried out in the absence of an HCI scavenger. Surprisingly, it has been found that compounds of Formula V are obtained in higher yields, if an HCI sequestering agent is not present in the reaction mixture.
[0119] As used herein, the term “HCI scavenger” refers to a chemical substance, which is added to a reaction mixture to remove or deactivate hydrogen chloride (HCI). HCI scavengers preferably include the bases, buffers and precursors of ionic liquids, which are defined in further detail below. Of particular interest is the ability of HCI scavengers to bind protons. HCI scavengers are preferably provided below.
[0120] Preferably, it should be understood that the term "HCI scavenger", as used herein, refers to a chemical substance, which is added to the reaction mixture and does not include the reaction starting materials, that is, the compounds of Formula (IVa) or (IVb).
[0121] Therefore, it is preferably that the reaction step (iv) is carried out in the absence of any additionally supplied chemical substance, which functions as an HCI scavenger.
[0122] Since the reaction step (iv) is preferably carried out in the absence of an HCI scavenger, the HCI produced is still in the reaction mixture when the hydrogenation catalyst is removed.
[0123] Therefore, in another preferred embodiment of process A, an HCI scavenger is added after removal of the hydrogenation catalyst. Preferably, the HCI scavenger is provided without water. It has been found that it is advantageous to maintain the reaction product, that is, the Formula V compounds, without water to prevent the loss of the compounds in the aqueous phase, to allow easier processing and to avoid the need to dry the compounds before other reactions.
[0124] The HCI scavenger which, preferably, is only added after the removal of the hydrogenation catalyst, mainly can be selected from bases, buffers, precursors of ionic liquids and their combinations.
[0125] The 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 alkali metal carbonates earth metals, alkali metal bicarbonates, alkali metal alkyls, alkylmagnesium halides, alkali metal alkaloids and alkaline earth metals and nitrogen-containing bases including tertiary amines, pyridines, bicyclic amines, ammonia and primary amines.
[0126] Buffers include aqueous and non-aqueous buffers and are preferably non-aqueous buffers. Buffers preferably include buffers based on acetate or formate, for example, sodium acetate or ammonium formate.
[0127] Ionic liquid precursors include imidazoles.
[0128] In a preferred embodiment of process A of the present invention, the HCI scavenger is selected from the group consisting of bases that include alkali metal alkali metal hydroxides, alkali metal and alkaline earth metal oxides , alkali metal and alkaline earth metal hydrides, alkali metal amides, alkali metal and alkaline earth metal carbonates, alkali metal bicarbonates, alkali metal alkyls, alkylmagnesium halides, alkali metal and alkaline earth metals, bases containing nitrogen including tertiary amines, pyridines, bicyclic amines, ammonia and primary amines, and combinations thereof; buffers including sodium acetate and / or ammonium formate; precursors of ionic liquids, including imidazoles; and their combinations.
[0129] In a preferred embodiment, the HCI scavenger comprises at least one base.
[0130] In an especially 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 hydroxide of calcium.
[0131] In another especially preferred embodiment, the base is selected from alkali metal and alkaline earth metal oxides, in particular, from the group consisting of lithium oxide, sodium oxide, calcium oxide and oxide magnesium.
[0132] In another especially preferred embodiment, the base is selected from hydrides of alkali metals and alkaline earth metals, in particular, from the group consisting of lithium hydride, sodium hydride, potassium hydride and hydride calcium.
[0133] In another especially preferred embodiment, the base is selected from alkali metal amides, in particular, from the group consisting of lithium amide, sodium amide and potassium amide
[0134] In another especially preferred embodiment, the base is selected from alkali metal and alkaline earth metal carbonates, in particular, from the group consisting of lithium carbonate and calcium carbonate.
[0135] In another especially preferred embodiment, the base is selected from alkali metal bicarbonates and, preferably, is sodium bicarbonate.
[0136] In another especially preferred embodiment, the base is selected from alkali metal alkyls, in particular, from the group consisting of methyl lithium, butyl lithium and phenyl lithium.
[0137] In another especially preferred embodiment, the base is selected from alkylmagnesium halides and, preferably, is methylmagnesium chloride
[0138] In another especially preferred embodiment, the base is selected from alkali metal and alkaline earth metal alcoholates, in particular, from the group consisting of sodium methanolate, sodium ethanolate, potassium ethanolate, ferc - potassium butanol and dimethoxymagnesium.
[0139] In another especially preferred embodiment, the base is a tertiary amine, in particular, trimethylamine, triethylamine, diisopropylethylamine or N-methylpiperidine.
[0140] In another especially preferred embodiment, the base is a pyridine including substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine.
[0141] In another embodiment, especially preferably, the base is a bicyclic amine.
[0142] In another embodiment, especially preferably, the base is ammonia.
[0143] In another embodiment, especially preferably, the base is a primary amine, in particular ethylamine.
[0144] In a most preferred embodiment of process A of the present invention, the HCI scavenger is potassium hydroxide or any of the carbonates defined above.
[0145] The bases can be used in equimolar amounts, in excess or, when appropriate, as solvents.
[0146] In another preferred embodiment, the HCI scavenger comprises at least one buffer.
[0147] In an especially preferred embodiment, the buffer is anhydrous sodium acetate or anhydrous ammonium formate.
[0148] In another preferred embodiment, the HCI scavenger comprises an precursor to an ionic liquid.
[0149] In an especially preferred embodiment, the ionic liquid precursor is an imidazole compound, which forms an ionic liquid after reacting with HCI, which is released in the hydrogenation / dehalogenation reaction. A non-polar organic phase comprising the desired pyridazine amine compound, therefore, can easily be separated from the newly formed ionic liquid.
[0150] As previously indicated above, any hydrogenation catalysts known in the art can be used for the reaction step (iv), in particular, the heterogeneous hydrogenation catalysts.
[0151] Hydrogenation catalysts preferably include platinum, palladium, rhodium, ruthenium, nickel or cobalt in vehicles, such as carbon.
[0152] In a preferred embodiment of process A of the present invention, the hydrogenation catalyst is selected from the group consisting of platinum or palladium on a support, Raney nickel, Raney cobalt and, preferably, platinum or palladium on carbon.
[0153] Optionally, the catalyst can be doped with sulfur or selenium. This can increase the selectivity of the catalyst.
[0154] In an especially preferred embodiment, the hydrogenation catalyst is palladium or platinum on carbon, where the palladium or platinum content is preferably in the range from 0.1 to 15% by weight, from preferably from 0.5 to 10% by weight based on the material of the vehicle.
[0155] In another especially preferred embodiment, the amount of palladium or platinum used is from 0.001 to 1% by weight, preferably from 0.01 to 0.1% by weight based on the starting material .
[0156] In an especially preferred embodiment, the hydrogenation catalyst is palladium on carbon, where the palladium content is preferably in the range from 0.1 to 15% by weight, most preferably at from 0.5 to 10% by weight based on the vehicle material. Furthermore, it is especially preferred that the amount of palladium used in the 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. It is especially preferred that 10% Pd / C is used in amounts from 0.01 to 0.1% by weight based on the amount of the starting material.
[0157] In another especially preferred embodiment, the hydrogenation catalyst is platinum on carbon, in which the platinum content is preferably from 0.1 to 15% by weight, most preferably from 0.5 to 10% by weight based on the vehicle material. In addition, it is especially preferred that the amount of platinum used in the reaction step (iv) is from 0.001 to 1, preferably from 0.01 to 0.1% by weight based on the material of departure. It is especially preferred that 10% Pt / C is used in an amount from 0.01 to 0.1% by weight based on the amount of the starting material.
[0158] In batch hydrogenation, the catalyst is preferably used in the form of a powder. In a continuous hydrogenation, the catalyst used in the carbon of the vehicle material is platinum or palladium.
[0159] After a reaction cycle, the catalyst can be removed through filtration and used again without noticeable loss of activity.
[0160] Regarding the starting materials of the reaction step (iv), it is emphasized that (a) a Formula IVa dichloropyridazine amine compound or a salt, tautomer or N-oxide thereof, or (b) a compound of dichloropyridazine amine of Formula IVb or a salt, tautomer or N-oxide thereof, or (c) a mixture of (a) and (b) can be used.
[0161] In a preferred embodiment of process A, a mixture of (a) and (b) is used.
[0162] The substituent R1 in the compounds of Formulas IVa, IVb and V is preferably selected from the group consisting of CH3, CH2CH3 and CH2OCH3.
[0163] In a preferred embodiment of process A, R1 in the compounds of Formulas IVa, IVb and V is CH2CH3.
[0164] In an especially preferred embodiment of process A, a mixture of (a) and (b) is used, and R1 in the compounds of Formulas IVa, IVb, and V is selected from the group consisting of CH3, CH2CH3 , and CH2OCH3, and, preferably, is CH2CH3.
[0165] The mild reaction conditions are preferably for the reaction step (iv).
[0166] In a preferred embodiment, the applied hydrogen pressure is in the range from 0.1 to 10 bar, preferably in the range from 0.1 to 1 bar, more preferably, in the range from from 0.1 to 0.5 bar. Higher pressures in the range from 0.6 bar to 10 bar, preferably from 1 bar to 5 bar can be advantageous if the starting material contains impurities in an amount greater than 2% by weight or greater than 5% in weight.
[0167] In a preferred embodiment, the reaction temperature is maintained within a range from 20 to 100 ° C, preferably in the range from 20 to 65 ° C. Preferably, the mixture of the reaction is heated to 30 to 40 ° C after the pressure reactor, in which the reaction is preferably carried out, is filled with hydrogen. However, since the hydrogenation reaction is exothermic, it may be necessary to cool the reaction mixture thereafter in order to maintain the temperature preferably below 60 ° C. It is especially preferably a reaction temperature in the range from 50 to 60 ° C.
[0168] Reaction times can vary over a wide range. The reaction times are preferably in the range from 1 hour to 12 hours, preferably in the range from 3 hours to 6 hours, for example, 4 or 5 hours.
[0169] Suitable solvents include water and aliphatic hydrocarbons, such as pentane, hexane, cyclohexane and light petroleum; 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 alkanols, such as ethylene glycol or propylene glycol; ether alkanols, such as diethylene glycol; carboxylic esters, such as ethyl acetate; N-methylpyrrolidone; dimethylformamide; and ethers, including open and cyclic ethers, especially diethyl ether, methyl tert-butyl ether (MTBE), 2-methoxy-2-methylbutane, cyclopentylmethylether, 1,4-dioxane, tetrahydrofuran and 2- methyltetrahydrofuran, in particular, tetrahydrofuran, MTBE and 2-methyltetrahydrofuran. Mixtures of said solvents can also be used.
[0170] The solvents are preferably protic solvents, preferably the alcohols selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol.
[0171] In a preferred embodiment, the solvent is a C1-C4 alcohol, in particular ethanol.
[0172] As described above, process A can not only comprise the reaction step (iv), but also other reaction steps of the reaction sequence described above.
[0173] In particular, process A, optionally, can still comprise step (iii) and optionally also step (ii), in which steps (ii) and (iiii) can be performed separately or in conjunction with steps (ii) + (iii) in a single vessel reaction. In addition, process A may optionally still comprise step (i). In addition, it should be understood that process A, optionally, can still comprise step (v).
[0174] In one embodiment of process A, the process further comprises reaction steps (ii) + (iii), that is, the step of preparing (a) dichloropyridazine amine compound of Formula IVa or a salt thereof, tautomer or N-oxide or (b) dichloropyridazine amine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c) mixture of (a) and (b)
in a single vessel reaction that comprises the steps through the reaction of a Formula II compound
with POCI3, and the reaction of the resulting crude reaction product with an amine compound R1-NH2 or a salt thereof, - where R1 is H, C1-C2 alkyl or C1-C2 alkoxy-C1-C2 alkoxy.
[0175] As indicated above, the single vessel reaction is advantageous since the obtained Formula III intermediate trichloropindazine compound, which is irritating, does not need to be isolated.
[0176] It should be understood that (a) or (b) or a mixture of (a) and (b) can be obtained in steps (ii) + (iii).
[0177] In a preferred embodiment, a mixture of (a) and (b) is obtained.
[0178] The substituent R1 in the compounds of Formulas IVa and IVb, and the amine compound R1-NH2, is preferably selected from the group consisting of CH3, CH2CH3 and CH2OCH3.
[0179] In a preferred embodiment, R1 in the compounds of Formulas IVa and IVb, and the amine compound R1-NH2 is CH2CH3.
[0180] In an especially preferred embodiment, a mixture of (a) and (b), and R1 is obtained in the compounds of Formulas IVa and IVb, and the amine compound R1-NH2 is selected from the group consisting of CH3, CH2CH3 and CH2OCH3, and, preferably, is CH2CH3.
[0181] It should be understood that the Formula II compound may also be present in the form of its pyridazone tautomer.
[0182] The reaction conditions for steps (ii) and (iii), which are carried out later in the single vessel reaction as defined above, without isolating the intermediate compound obtained from Formula III, are defined in more detail below.
[0183] In an alternative embodiment of process A, the process further comprises the reaction step (iii), that is, the preparation step (a) of the Formula IVa dichloropyridazine amine compound or a salt, tautomer or N -oxide, or (b) the Formula IVb dichloropyridazine amine compound or a salt, tautomer or N-oxide thereof, or (c) the mixture of (a) and (b)
through the reaction of a Formula III trichloropyridazine compound
with an amine compound R1-NH2 or a salt thereof, where R1 is H, C1-C2 alkyl or C1-C2 alkoxy-C1-C2 alkyl, and where reaction step (ii), that is, trichloropyridazine Formula III
through the reaction of a Formula II compound
with POCI3.
[0184] In accordance with this embodiment, the compound of Formula III is isolated which, for example, can be carried out through precipitation.
[0185] It should be understood that (a) or (b) or a mixture of (a) and (b) can be obtained in steps (iii).
[0186] In a preferred embodiment, a mixture of (a) and (b) is obtained.
[0187] The substituent R1 in the compounds of Formulas IVa and IVb, and the amine compound R1-NH2, is preferably selected from the group consisting of CH3, CH2CH3 and CH2OCH3.
[0188] In a preferred embodiment, R1 in the compounds of Formulas IVa and IVb, and the amine compound R1-NH2 is CH2CH3.
[0189] In an especially preferred embodiment, a mixture of (a) and (b), and R1 is obtained in the compounds of Formulas IVa and IVb, and the amine compound R1-NH2 is selected from the group consisting of CH3, CH2CH3 and CH2OCH3 and, preferably, is CH2CH3.
[0190] As indicated above above, it should be understood that the compound of Formula II may also be present in the form of its pyridazone tautomer.
[0191] The reaction conditions for steps (ii) and (iii), which also apply to the situation, where the steps are performed as steps (ii) + (iiii) in a single vessel reaction are defined below.
[0192] The reaction conditions for step (ii) are preferably as follows.
[0193] In a preferred embodiment of the reaction step (ii), POCI3 is used in excess.
[0194] In another preferred embodiment, POCI3 is used in an amount from at least 1.5 mol per mol of the compound of Formula II.
[0195] In an especially preferred embodiment, POCI3 is used in an amount from 1.5 to 2.0 mol per mol of the compound of Formula II.
[0196] In another especially preferred embodiment, POCI3 is used in an amount greater than 2.0 to 10 mol per mol of the compound of Formula II, preferably in an amount from 4.0 to 6.0 mol, especially in an amount from 4.8 to 5.2 mol per mol of the compound of Formula II.
[0197] In yet another especially preferred embodiment, POCI3 is used as a solvent for the reaction step (ii).
[0198] Preferably, the reaction step (ii) is carried out in the absence of a solvent.
[0199] It is also preferable that the reaction is carried out in a protective gas atmosphere, for example, under nitrogen.
[0200] The reaction temperature can be in the range from 60 ° C to 130 ° C, preferably in the range from 100 ° C to 125 ° C.
[0201] Reaction times may vary over a wide range, and are preferably between 1 hour and 24 hours, preferably in the range from 1 hour to 5 hours, most preferably in the range from 1 hour to 2 hours.
[0202] After the reaction, excess POCI3 can be removed under reduced pressure. Then, preferably, water is added to the reaction mixture after cooling, so that the temperature preferably does not exceed 30 ° C.
[0203] The Formula III trichloropyridazine compound can be isolated as a precipitate from the aqueous phase, or by transferring the Formula III compound into an organic phase and removing the organic solvent.
[0204] Preferred organic solvents in this context include dichloromethane, iso-butanol, ethyl acetate and butyl acetate, in particular, butyl acetate.
[0205] Regarding the preparation and isolation of the trichloropyridazine compound of Formula III, for example, reference is made to publications WO 2013/004984, WO 2014/091368, WO 1999/64402, WO 2002/100352, and Russian Journal of Applied Chemistry, Volume 77, No.12, 2004, pages 1,997-2,000.
[0206] If the single vessel reaction procedure, as defined above, is performed, the step of isolating the Formula III trichloropyridazine compound can be omitted. Instead, trichloropyridazine is transferred to an organic phase and used directly in the next reaction step.
[0207] Preferred organic solvents in this context include dichloromethane, iso-butanol, ethyl acetate and butyl acetate, in particular, butyl acetate.
[0208] The organic phase can optionally be washed with a solution of sodium hydroxide in water (for example, a 10% aqueous solution of NAOH) and / or water before further use.
[0209] The reaction conditions for step (iii) are preferably as follows.
[0210] Depending on the substituent R1, the amine compound R1- NH2 can be in gaseous or liquid or solid form. If the amine compound R1-NH2 is in gaseous form, it can be supplied as a solution or as a gas.
[0211] An amine compound especially preferably is ethylamine as indicated above above.
[0212] Suitable solvents include protic solvents, preferably water or C1-C4 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, especially ethanol.
[0213] In a preferred embodiment, the solvent, in which the amine compound R1-NH2 is provided, is water. Suitable concentrations are in the range from 10 to 100% by weight based on the total weight of the solution, preferably in the range from 40 to 90% by weight, most preferably from 60 to 80%, most preferably, from 66 to 72% by weight.
[0214] In an especially preferred embodiment, the amine compound R1-NH2 is ethylamine and is supplied as a solution in water with a concentration in the range from 60 to 80% based on the total weight of the solution, preferably , from 66 to 72% by weight.
[0215] It is a surprising discovery of the present invention that the presence of water in the reaction mixture does not negatively affect the yields of the reaction step (iii).
[0216] In another preferred embodiment, the amine compound R1-NH2 is supplied in gaseous form and is introduced into the reaction mixture by bubbling through the solvent, in which the reaction step (iii) must be carried out, and in which the trichloropyridazine compound of Formula III can be dissolved. In this context, the solvents preferably include the protic solvents, preferably the alcohols selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol. Especially preferably it is ethanol as the solvent. In addition, solvents preferably, in which the gaseous amine compound R1-NH2 can be dissolved for the reaction step (iii), in general, include toluene, THF and ethanol.
[0217] Preferably, an excess of the amine compound R1-NH2 is used.
[0218] In a preferred embodiment, the amine compound R1- NH2 is used in an amount from 1.5 to 10 mol per mol of the compound of Formula III, preferably in an amount from 2.0 to 6.0 mol, especially in an amount from 2.0 to 3.0 mol per mol of the compound of Formula III.
[0219] Suitable solvents for the reaction include water and aliphatic hydrocarbons such as pentane, hexane, cyclohexane and light petroleum; aromatic hydrocarbons such as toluene, o-, m- and p-xylene; halogenated hydrocarbons such as methylene chloride, chloroform and chlorobencozene; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol; C2-C4 alkanols, such as ethylene glycol or propylene glycol; ether alkanols such as diethylene glycol; carboxylic esters such as ethyl acetate; N-methylpyrrolidone; dimethylformamide; and ethers, including open and cyclic ethers, especially diethyl ether, methyl-tert-butyl-ether (MTBE), 2-methoxy-2-methylbutane, cyclopentylmethylether, 1,4-dioxane, tetrahydrofuran and 2- methyltetrahydrofuran, in particular tetrahydrofuran, MTBE and 2-methyltetrahydrofuran. Mixtures of said solvents can also be used.
[0220] It is especially preferable that the reaction is carried out in a mixture of solvents, in which the starting materials are provided, for example, a mixture of water and butyl acetate.
[0221] Alternatively, it is, especially preferably, that the reaction is carried out in protic solvents, preferably the alcohols selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol and ferc -butanol, especially ethanol, especially if the amine compound is supplied in gaseous form. The reaction step (iii), therefore, will be carried out in this protic solvent and, optionally, also the reaction step (iv) can be carried out directly after in a single vessel reaction, optionally with the excess of the amine compound used as the HCI hijacker.
[0222] The reaction can be carried out at temperatures in the range from 0 ° C to 140 ° C, preferably in a range from 25 ° C to 60 ° C, more preferably, in a range from 30 ° C to 50 ° C.
[0223] In the context with the amine compound R1-NH2, as defined herein, especially with the amine compound R1-NH2 being ethylamine, the following reaction temperatures are especially preferred.
[0224] In one embodiment, the reaction step (iii) is carried out at a temperature of 100 ° C or less.
[0225] In another embodiment, the reaction step (iii) is carried out at a temperature of 80º C or less.
[0226] In another embodiment, the reaction step (iii) is carried out at a temperature of 70º C or lower.
[0227] In another embodiment, the reaction step (iii) is carried out at a temperature of 60º C or less.
[0228] In one embodiment, the reaction step (iii) is carried out at a temperature of 0 ° C to 100 ° C.
[0229] In another embodiment, the reaction step (iii) is carried out at a temperature of 0 ° C to 80 ° C.
[0230] In another embodiment, the reaction step (iii) is carried out at a temperature of 0 ° C to 70 ° C.
[0231] In another embodiment, the reaction step (iii) is carried out at a temperature of 0 ° C to 60 ° C.
[0232] In a preferred embodiment, the reaction step (iii) is carried out at a temperature of 20 ° C to 80 ° C.
[0233] In another preferred embodiment, the reaction step (iii) is carried out at a temperature of 20 ° C to 70 ° C.
[0234] In another preferred embodiment, the reaction step (iii) is carried out at a temperature of 20 ° C to 60 ° C.
[0235] In an especially preferred embodiment, the reaction step (iii) is carried out at a temperature of 25 ° C to 60 ° C.
[0236] 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, in particular, from 1 hour to 12 hours. Most preferably, the reaction time is in the range from 1 hour to 5 hours preferably from 3 hours to 4 hours.
[0237] In the context of the reaction step (iii), reference is also made to US patent 4,728,355.
[0238] As indicated above above, process A may optionally still comprise step (i) to provide the compound of Formula II.
[0239] In an implementation of process A, the process comprises, in addition to steps (ii) and (iii), carried out separately or as a single vessel reaction, also step (i), that is, the process still comprises the preparation stage of the compound of Formula II
through the reaction of mucochloric acid I
with hydrazine or a salt thereof.
[0240] The reaction conditions for step (iii) are preferably as follows.
[0241] The reagents are preferably supplied in similar amounts, for example, in a molar ratio from 1.5: 1 to 1: 1.5, preferably in equimolar amounts.
[0242] Hydrazine is preferably supplied in the form of a salt, preferably as hydrazine sulfate.
[0243] Suitable solvents include protic solvents such as water.
[0244] The reaction mixture is preferably heated to 100 ° C, until a precipitate is formed.
[0245] For further details, reference is made to US patent 4,728,355.
[0246] As previously indicated above, process A can optionally still comprise step (v).
[0247] In one embodiment of process A, the process still comprises step (v), that is, the process still comprises the step of converting the Formula V pyridazine amine compound or a salt, tautomer or N-oxide thereof in a compound of Formula VII or a stereoisomer, salt, tautomer or N-oxide
through the reaction of the Formula V pyridazine amine compound or a salt, tautomer or N-oxide thereof
with a compound of Formula VI or a stereoisomer, salt, tautomer or N-oxide
where R1 is H, C1-C2 alkyl or C1-C2 alkoxy-C1-C2 alkyl, and where R2 is H, halogen, CN, NO2, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl, where The last 3 radicals mentioned can be unsubstituted, can be partially or totally halogenated or can carry 1,2 or 3 identical or different Rx substituents, or ORa, SRa, C (Y) Rb, C (Y) ORC, S (O) Rd, S (O) 2Rd, NReRf, C (Y) NRgRh, heterocyclyl, hetaryl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl or phenyl, where the last five radicals mentioned may be unsubstituted or may carry 1, 2, 3, 4 or 5 identical or different substituents selected from the radicals Ry and Rx; R3 is H, halogen, CN, NO2, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl, where the last 3 radicals mentioned may be unsubstituted, may be partially or fully halogenated or may carry 1,2 or 3 identical or different Rx substituents, or ORa, SRa, C (Y) Rb, C (Y) ORC, S (O) Rd, S (O) 2Rd, NReRf, C (Y) NRgRh, heterocyclyl, hethyl, cycloalkyl C3-C10, C3-C10 cycloalkenyl or phenyl, wherein the last five radicals mentioned may be unsubstituted or may carry 1, 2, 3, 4 or 5 identical or different substituents selected from the radicals Ry and Rx; RN is H, CN, NO2, C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl, where the last three radicals mentioned may be unsubstituted, may be partially or totally halogenated or may carry 1,2 or 3 identical or different Rx substituents, or ORa, SRa, C (Y) Rb, C (Y) ORC, S (O) Rd, S (O) 2Rd, NReRf, C (Y) NR9Rh, S (O) mNReRf, C (Y) NR'NReRf, C1-Cs-ORa alkylene, C1-C5-CN alkylene, C1-Cs-C alkylene (Y) Rb, C1-Cs-C (Y) alkylene ORC, C1-Cs-NReRf alkylene, C1-Cs-C (Y) alkylene NR9Rh, C1-C5-S alkylene (0) mRd, C1-C5-S (O) mNReRf alkylene, C1-C5-NR'NReRf alkylene, heterocyclyl, hethyl, C3-C10 cycloalkyl , C3-C10 cycloalkenyl, C1-C5 heterocyclyl-alkyl, C1-C5 hetero-alkyl, Cs-Cw-C1-C5 cycloalkyl, C1-C5-C5 cycloalkenyl, C1-C5-phenyl-C1-C5 or phenyl, on whereas the rings of the last ten radicals mentioned may be unsubstituted or may carry 1, 2, 3, 4 or 5 identical or different Ry substituents; and where Ra, Rb, Rc, independently of each other, are selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C3-C6 halocycloalkyl, C2-C4 alkenyl, halo C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy-C1-C4 alkyl, heterocyclyl, C1-C4 heterocyclyl, phenyl, hetaryl, C1-C4-phenyl-alkyl and C1-C4-heteryl-alkyl, where the ring in the last six radicals mentioned can be unsubstituted or can carry 1,2, 3, 4 or 5 substituents which, independently of each other, are selected from halogen, CN, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy; Rd is selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C3-C6 halocycloalkyl, C2-C4 alkenyl, C2-C4 haloalkyl, C2-C4 alkoxy, C2-C4 alkoxy -C1-C4 alkyl, heterocyclyl, heterocyclyl-C1-C4 alkyl, phenyl, hetaryl, phenyl-C1-C4 alkyl or C-C4 hetaryl-alkyl, where the ring in the last six mentioned radicals may be unsubstituted or may carry 1 , 2, 3, 4 or 5 substituents which, independently of each other, are selected from halogen, CN, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy; Re, Rf, independently of each other, are selected from H, C1-C4 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, C1-C4-alkylcarbonyl, C1-C4-haloalkylcarbonyl, C1-C4-alkylsulfonyl, C1-C4-haloalkylsulfonyl, heterocyclyl, C1-C4-alkyl, heterocyclyl, heterocyclyl, heterocyclyl, heterocyclyl , phenylcarbonyl, phenylsulfonyl, heteroaryl, heteroarbonyl, heteroarylsulfonyl, phenyl-C1-C4-alkyl and C1-C4-heteryl-alkyl, where the ring in the last 12 mentioned radicals can be unsubstituted or can carry 1, 2, 3, 4 or 5 substituents that, independently of each other, are selected from halogen, CN, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy; or Re and Rf together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocycle, which can carry an additional heteroatom to be selected from O, S and N as an atom of the member of the ring and in which the heterocycle can be unsubstituted or can carry 1, 2, 3, 4 or 5 substituents which, independently of each other, are selected from halogen, CN, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy; Rg, Rh, independently of each other, are selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C2-C4 alkenyl, C2-C4 haloalkyl, C2-C4 alkynyl, C1-4 alkoxy-C4-alkyl, heterocyclyl, heterocyclyl-C1-C4-alkyl, phenyl, hetaryl, phenyl-C1-C4-alkyl and heteryl-C1-C4-alkyl, where the ring in the last six mentioned radicals may be unsubstituted or they can carry 1, 2, 3, 4 or 5 substituents which, independently of each other, are selected from halogen, CN, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy; R 'is selected from H, C1-C4 alkyl, C-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylmethyl, C3-C6 halocycloalkyl, C2-C4 alkenyl, C2-C4 haloalkyl, C2-C4 alkenyl -alkynyl, C1-4 alkoxy-C1-4 alkyl, phenyl and C1-4 alkyl phenyl-alkyl, in which the phenyl ring in the last two radicals mentioned can be unsubstituted or can carry 1, 2, 3, 4, or 5 substituents that, independently of each other, are selected from halogen, CN, NO2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy; Rx is selected from CN, NO2, C1-C4 alkoxy, C1-C4 haloalkoxy, S (0) mRd, S (O) mNReRf, C1-C10 alkylcarbonyl, C1-C4 haloalkylcarbonyl, C1-C4 alkoxycarbonyl, C1-4 alkoxycarbonyl C4, C3-C6 cycloalkyl, 5- to 7-membered heterocyclyl, 5- or 6-membered heterocyclyl, phenyl, C3-C6 cycloalkoxy, 3- to 6-membered heterocyclyl and phenoxy, where the last 7 radicals mentioned may be unsubstituted or may carry 1,2, 3, 4 or 5 Ry radicals; Ry is selected from halogen, CN, NO2, C-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, S (O) mRd, S (O) mNReRf, C1-C4 alkylcarbonyl, haloalkylcarbonyl C1-C4, C1-C4 alkoxycarbonyl, C1-C4 haloalkoxycarbonyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C2-C4 alkenyl, C2-C4 haloalkenyl, C2-C4 alkynyl, and C-C4-alkoxy C1-alkyl, C1-alkyl and where Y is O or S; em is 0, 1 or 2; and where X1 is an leaving group which is preferably selected from halogen, N3, p-nitrophenoxy and pentafluorophenoxy.
[0248] In a preferred embodiment, R1 is CH2CH3; R2 is C1-C4 alkyl, which may be unsubstituted, or may be partially or fully halogenated; R3 is H; and RN is a -CR4R5R6 group in which R4 is selected from C1-C4 alkyl, which may be unsubstituted, may be partially or fully halogenated, or may carry 1 or 2 identical or different Rx substituents, in which Rx is selected from CN and C (O) NH2 and C3-C6 cycloalkyl, which can be unsubstituted or can carry 1, 2 or 3 identical or different Ry substituents, where Ry is selected from halogen, CN and C (O ) NH2; and R5 is selected from C1-C4 alkyl, which can be unsubstituted, can be partially or fully halogenated, or can carry 1 or 2 identical or different Rx substituents, where Rx is selected from CN and C (O ) NH2, and C3-C6 cycloalkyl, which can be unsubstituted or can carry 1, 2 or 3 identical or different Ry substituents, where Ry is selected from halogen, CN and C (O) NH2; or R4 and R5 together with the carbon atom to which they are attached form a saturated non-aromatic carbocycle with 3 to 12 members, which can be partially or completely replaced by RJ, where Ri is selected from halogen, CN and C (O) NH2; and R6 is H; and X1 is an leaving group which is preferably selected from halogen, N3, p-nitrophenoxy and pentafluorophenoxy and, especially preferably, is chlorine.
[0249] In one embodiment, most preferably, RN is -CR4R5R6, and 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 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, R3 is H, R4 is 1-CN-CC3H4, R5 is CH3 and R6 is H; or R2 is CH3, R3 is O H, R4 is O 1-C (O) NH2-CC3H4, R5 is O CH3 and R6 is 0 H; or R2 is 0 CH3, R3 is H, R4 and R5, together, are CH2CH2CF2CH2CH2 and R6 is H; and X1 is a leaving group, which is preferably selected from halogen, N3, p-nitrophenoxy and pentafluorophenoxy, and is especially preferably chlorine.
[0250] Regarding the reaction conditions for step (v), reference is made to the publications WO 2009/027393 and WO 2010/034737.
[0251] In the following, preferred embodiments are provided in relation to process B of the present invention. It is to be understood that the preferred embodiments mentioned above and those that are still illustrated below process B of the present invention are to be understood as preferably alone or in combination with each other.
[0252] As indicated above above, the present invention relates in a second aspect to process B of preparation (a) of a formula IVa dichloropyridazine amine compound or a salt, tautomer or N-oxide thereof, or (b ) of a dichloropyridazine amine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c) a mixture of (a) and (b)
in a single vessel reaction that comprises the steps of the reaction of a Formula II compound
with POCI3, and the reaction of the resulting crude reaction product with an amine compound R1-NH2 or a salt thereof, wherein R1 is H, C1-C2 alkyl or C1-C2 alkoxy-C1-C2 alkoxy.
[0253] The reaction step underlying process B corresponds to steps (ii) + (iii) in the reaction sequence above.
[0254] As indicated above, the single vessel reaction is advantageous, since the intermediate obtained the Formula III trichloropindazine compound, which is an irritant, does not need to be isolated.
[0255] As indicated above above, it should be understood that the Formula II compound may also be present in the form of its pyridazone tautomer.
[0256] It should be understood that (a) or (b) or a mixture of (a) and (b) can be obtained in steps (ii) + (iii).
[0257] In a preferred embodiment, a mixture of (a) and (b) is obtained.
[0258] The substituent R1 in the compounds of Formulas IVa and IVb, and the amine compound R1-NH2, is preferably selected from the group consisting of CH3, CH2CH3 and CH2OCH3.
[0259] In a preferred embodiment, R1 in the compounds of Formulas IVa and IVb, and the amine compound R1-NH2 is CH2CH3.
[0260] In an especially preferred embodiment, a mixture of (a) and (b), and R1 is obtained in the compounds of Formulas IVa and IVb, and the amine compound R1-NH2 is selected from the group consisting of CH3, CH2CH3 and CH2OCH3, and, preferably, is CH2CH3.
[0261] The reaction conditions for steps (ii) and (iii), which are carried out later in the single vessel reaction, as defined above, without isolating the intermediate compound obtained from Formula III, were provided above above.
[0262] In a preferred embodiment of process B, the process still comprises step (i), that is, the step of preparing the compound of Formula II
through the reaction of mucochloric acid (I)
with hydrazine or a salt thereof.
[0263] The reaction conditions for this reaction step (i) were provided above above.
[0264] In another preferred embodiment of process B, the process further comprises step (iv), that is, the conversion step (a) of the Formula IVa dichloropyridazine amine compound or a salt, tautomer or N- oxide, or (b) the dichloropyridazine amine composed of Formula IVb or a salt, tautomer or N-oxide thereof, or (c) a mixture of (a) and (b) in a Formula V pyridazine amine compound or a salt, tautomer or N-oxide
by reaction (a) of the formula IVa dichloropyridazine amine compound or a salt, tautomer or N-oxide thereof, or (b) the formula IVb dichloropyridazine amine compound or a salt, tautomer or N-oxide thereof, or (c) the mixture of (a) and (b)
with hydrogen in the presence of a dehydrogenation catalyst, where R1 is as defined above; and wherein the process optionally comprises step (v), that is, the step of converting the Formula V pyridazine amine compound or a salt, tautomer or N-oxide thereof to a Formula VII compound or a compound thereof stereoisomer, salt, tautomer or N-oxide
through the reaction of the Formula V pyridazine amine compound or a salt, tautomer or N-oxide thereof
with a compound of Formula VI or a stereoisomer, salt, tautomer or N-oxide
where R1 is as defined above, and where R2, R3, RN and X1 are as defined above.
[0265] The preferred realizations and reaction conditions for reaction steps (iv) and (v) were provided above above in context with process A.
[0266] In the following, the embodiments are preferably provided in relation to process C of the present invention. It is to be understood that the embodiments, preferably mentioned above and those that are still illustrated below in process C of the present invention are to be understood as preferably alone or in combination with each other.
[0267] As indicated above above, the present invention relates, in a third aspect, to process C of preparation (a) of a Formula IVa dichloropyridazine amine compound or a salt, tautomer or N-oxide thereof, or (b) a Formula IVb dichloropyridazine amine compound or a salt, tautomer or N-oxide thereof, or (c) a mixture of (a) and (b)
which comprises the reaction step of a Formula III trichloropyridazine compound
with an amine compound R1-NH2 or a salt thereof, where R1 is CH2CH3, and where the process optionally still comprises the step of preparing the Formula III trichloropyridazine compound
through the reaction of a Formula II compound
with POCI3.
[0268] The reaction process underlying process C covers step (iii) in the above reaction sequence and optionally in addition to step (ii) as a separate step.
[0269] Surprisingly, it has been found that especially high yields can be obtained in the reaction step (iii), if ethylamine is used as the amine compound R1-NH2. Furthermore, laborious processing is not necessary.
[0270] As indicated above above, it should be understood that the compound of Formula II may also be present in the form of its pyridazone tautomer.
[0271] It should be understood that (a) or (b) or a mixture of (a) and (b) can be obtained in step (iii).
[0272] In a preferred embodiment, a mixture of (a) and (b) is obtained.
[0273] The reaction conditions for steps (ii) and (iii), which are carried out separately according to process C, were previously provided above.
[0274] In a preferred embodiment of process C, the process further comprises step (i), that is, the step of preparing the compound of Formula II
through the reaction of mucochloric acid (I)
with hydrazine or a salt thereof.
[0275] The reaction conditions for this reaction step (i) were provided above above.
[0276] In another preferred embodiment of process C, the process further comprises step (iv), that is, the conversion step (a) of the Formula IVa dichloropyridazine amine compound or a salt, tautomer or N- oxide, or (b) the dichloropyridazine amine composed of Formula IVb or a salt, tautomer or N-oxide thereof, or (c) a mixture of (a) and (b) in a Formula V pyridazine amine compound or a its salt, tautomer or N-oxide
by reaction (a) of the formula IVa dichloropyridazine amine compound or a salt, tautomer or N-oxide thereof, or (b) the formula IVb dichloropyridazine amine compound or a salt, tautomer or N-oxide thereof , or (c) the mixture of (a) and (b)
with hydrogen in the presence of a hydrogenation catalyst, where R1 is as defined above; and wherein the process optionally further comprises step (v), that is, the step of converting the Formula V pyridazine amine compound or a salt, tautomer or N-oxide thereof to a Formula VII compound or a its stereoisomer, salt, tautomer or N-oxide
through the reaction of the Formula V pyridazine amine compound or a salt, tautomer or N-oxide thereof
with a compound of Formula VI or a stereoisomer, salt, tautomer or N-oxide
where R1 is as defined above, and where R2, R3, RN and X1 are as defined above.
[0277] The preferred realizations and reaction conditions for the reaction steps (iv) and (v) were provided above above in the context with process A.
[0278] In the following, the embodiments are preferably provided in relation to process D of the present invention. It is to be understood that the embodiments, preferably, mentioned above and those that are still illustrated below process D of the present invention are to be understood as, preferably, alone or in combination with each other.
[0279] As indicated above, the present invention relates, in an additional aspect, to a D process for the preparation of a compound of Formula VII * or a stereoisomer thereof, salt, tautomer or N-oxide
comprising the reaction step of a Formula V pyridazine amine compound or a salt, tautomer or N-oxide thereof
with a compound of Formula VI * or a stereoisomer, salt, tautomer or N-oxide
wherein R1 is CH2CH3; and wherein R2 is CH3, R3 is H, R4 is CH3, R5 is CH3 and R5 is H; or R2 is CH3, R3 is OH, R4 is CF3, R5 is CH3 and RS is OH; OR R2 is CH3, R3 is OH, 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, 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, they are CH2CH2CF2CH2CH2 and R6 is H; and where X1 is an leaving group which is preferably selected from halogen, N3, p-nitrophenoxy and pentafluorophenoxy and, especially preferably, is chlorine.
[0280] The reaction step underlying process D is covered by step (v) of the above reaction sequence.
[0281] In a preferred embodiment, the process still comprises step (iv) of the reaction sequence.
[0282] In a most preferred embodiment, the process still comprises step (iii) and optionally also step (ii), in which steps (ii) and (iii) can be carried out separately by isolating the Formula III, or in combination in a single vessel reaction.
[0283] In an even more preferred embodiment, the process still comprises step (i).
[0284] Further details regarding steps (i), (ii), (iii) and (iv) have been provided above.
[0285] As indicated above above, the present invention relates to another aspect for a dichloropyridazine amine compound of Formula IVa or a salt, tautomer or N-oxide thereof;
wherein R1 is CH2CH3; or a dichloropyridazine amine compound of Formula IVb or a salt, tautomer or N-oxide thereof,
where R1 is CH2CH3.
[0286] In another aspect, the present invention relates to a mixture of the Formula IVa dichloropyridazine amine compound or a salt, tautomer or N-oxide thereof and to the Formula IVb dichloropyridazine amine compound or a salt thereof, tautomer or N-oxide as defined above, that is, where R1, in each case, is CH2CH3.
[0287] These compounds are the valuable starting materials for the preparation of 4-ethylamino-pyridazine, which alone, for example, can be converted into 4-pyrazol-N-pyridazinamide compounds active as Formula VII pesticides.
[0288] Typically, the mixture of the Formula IVa dichloropyridazine amine compound or a salt, tautomer or N-oxide thereof and the Formula IVb dichloropyridazine amine compound or a salt, tautomer or N-oxide thereof as defined above, that is, where R1, in each case, is CH2CH3 can be obtained through processes B or C, as described herein. The mixtures can be separated into components (a) dichloropyridazine amine compound of Formula IVa or a salt, tautomer or N-oxide thereof and (b) in the dichloropyridazine amine compound of Formula IVb or a salt, tautomer or N -oxide through separation techniques known to the person skilled in the art, for example, through column chromatography. However, separation of the two components is not necessary for the preparation of the Formula V pyridazine amine compound, since both components are suitable starting materials for the dehalogenation / hydrogenation reaction.
[0289] In the mixture, components (a) of the Formula IVa dichloropyridazine amine compound or a salt, tautomer or N-oxide thereof and (b) of the Formula IVb dichloropyridazine amine compound or a salt, tautomer thereof or N-oxide can be present in any proportion, preferably in a weight ratio range from 100: 1 to 1: 100, preferably from 10: 1 to 1:10, more preferably from 5 : 1 to 1: 5, most preferably from 2: 1 to 1: 2, especially even more preferably, from 1: 1. EXAMPLES I. CHARACTERIZATION
[0290] The characterization can be carried out through coupled High Performance Liquid Chromatography / mass spectrometry (HPLC / MS), through NMR or through its melting points.
[0291] HPLC: Agilent Extend 1.8 pm C18 4.6 x 100 mm; mobile phase: A: water + 0.1% H3PO4; B: acetonitrile (MeCN) + 0.1% H3PO4; gradient: from 5 to 95% A in 10 minutes; 0 to 10 minutes is 5:95 A: B, then gradient from 10 to 10.1 minutes at 95: 5 flow A: B: 1.2 mL / min in 10 minutes at 60 ° C.
[0292] NMR 1H: the signals are characterized through chemical change (ppm) versus tetramethylsilane, through their multiplicity and through their integral number (relative number of hydrogen atoms provided). The following abbreviations are used to characterize the multiplicity of signs: m = multiple, q = quartet, t = triplet, d = doublet and s = singlet.
[0293] The abbreviations used are: h for hour (s), min for minute (s) and room temperature from 20 to 25 ° C. II. PREPARATION EXAMPLES (1) Preparation of a mixture of 3,4-dichloro-5-ethylaminopyridazine and 3,5-dichloro-4-ethylaminopyridazine in a one-step procedure starting from 4,5-dichloro-3-hydroxypyridazine:
[0294] 200 g of 4,5-dichloro-3-hydroxypyridazine were placed in a reactor at 20 ° C under N2 and POCI3 (930 g, 5 equiv.) 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. The excess of POCI3 was removed by distillation. The reaction mixture was dosed in 1,200 g of H2O controlling the temperature at 30 ° C. Butyl acetate (1,200 g) was added and the biphasic mixture was stirred for 30 minutes at 30 ° C and then the phases were separate. Another portion of butyl acetate (400 g) was added to wash the aqueous phase. The combined organic phases were washed with 10% HCI and then with H2O.
[0295] To the mixture of trichloropyridazine in butyl acetate was added a solution of ethylamine in water with a concentration of 70% by weight of ethylamine based on the total weight of the solution (234 g, 3 equiv) at 35 ° C. The reaction was maintained at 45 ° C for 3 hours (or until full 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. Butyl acetate from the combined organic phases was distilled (15 mbar, 35 ° C) to concentrate the reaction mixture. During this process, the product precipitated out of solution. The reaction mixture was cooled to 10 ° C and the product was removed through filtration. The mother liquor was then concentrated and the crude material was crystallized again from MTBE to isolate the rest of the product. (2) Preparation of 4-ethylaminopyridazine:
[0296] 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 were 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. Since the reaction is exothermic, the temperature was controlled at 55 ° C for 4 hours. Then the pressure was released and the reactor was purged with N2. The reaction mixture was filtered at room temperature to remove the catalyst. The catalyst can be used again in the next batch without purification.
[0297] In a second reactor, a mixture of K2CO3 (1 kg) and 1 liter of EtOH was prepared. The reaction mixture was dosed in the potassium carbonate solution over 60 minutes and the temperature was controlled at 20 to 25 ° C. The reaction mixture was further stirred for 3 hours. The salts produced in the process were removed by filtration. A solvent portion of the reaction mixture was separated by distillation and MTBE was added to precipitate pure ethylaminopyridazine (354 g, 91% purity, 85% yield).

权利要求:
Claims (12)
[0001]
1. PROCESS FOR THE PREPARATION OF A Pyridazine AMINE COMPOUND OF FORMULA V OR A SALT, TAUTOMER OR N-OXIDE
[0002]
2. PROCESS according to claim 1, characterized in that the reaction is carried out in the absence of an HCl scavenger.
[0003]
PROCESS according to any one of claims 1 to 2, characterized in that an HCl scavenger is added after removal of the hydrogenation catalyst, wherein the HCl scavenger is preferably supplied without water.
[0004]
PROCESS according to any one of claims 1 to 3, characterized in that the HCl scavenger is selected from the group consisting of bases that include alkali metal and alkaline earth metal hydroxides, alkali metal and metal oxides alkaline earth, hydrides of alkali metals and alkaline earth metals, amides of alkali metals, carbonates of alkali metals and alkaline earth metals, alkali metal bicarbonates, alkali metal alkyls, alkylmagnesium halides, alkali metals and alkali metals earthy, nitrogen-containing bases including tertiary amines, pyridines, bicyclic amines, ammonia and primary amines; and their combinations; buffers including sodium acetate and / or ammonium formate; precursors of ionic liquids, including imidazois; and their combinations.
[0005]
PROCESS according to any one of claims 1 to 4, characterized in that the hydrogenation catalyst is selected from the group consisting of platinum or palladium in a vehicle, Raney nickel and Raney cobalt and, preferably, be platinum or carbon palladium.
[0006]
6. PROCESS according to any one of claims 1 to 5, characterized in that R1 is CH2CH3.
[0007]
PROCESS according to any one of claims 1 to 6, characterized in that it additionally comprises a step of preparing the compound of Formula II
[0008]
PROCESS according to any one of claims 1 to 7, characterized in that it further comprises the step of converting the pyridazine amine compound of Formula V or a salt, tautomer or N-oxide thereof to a compound of Formula VII or a its stereoisomer, salt, tautomer or N-oxide
[0009]
9. PROCESS, according to claim 8, characterized in that: - R1 is CH2CH3; - R2 is C1-C4 alkyl, which may be unsubstituted, or may be partially or fully halogenated; - R3 is H; and where RN is a -CR4R5R6 group in which - R4 is selected from C1-C4 alkyl, which can be unsubstituted, can be partially or fully halogenated, or can carry 1 or 2 identical or different Rx substituents, where Rx is selected from CN and C (O) NH2 and C3-C6 cycloalkyl, which can be unsubstituted or can carry 1, 2 or 3 identical or different Ry substituents, where Ry is selected from halogen, CN and C (O) NH2; and - R5 is selected from C1-C4 alkyl, which can be unsubstituted, can be partially or fully halogenated, or can carry 1 or 2 identical or different Rx substituents, where Rx is selected from CN and C ( O) NH2, and C3-C6 cycloalkyl, which can be unsubstituted or can carry 1, 2 or 3 identical or different Ry substituents, where Ry is selected from halogen, CN and C (O) NH2; or - R4 and R5 together with the carbon atom to which they are attached form a 3 to 12 membered non-aromatic saturated carbocycle, which can be partially or completely replaced by Rj, where Rj is selected from halogen, CN and C (O) NH2; and - R6 and H; and wherein X1 is a saphenous group which is preferably selected from halogen, N3, p-nitrophenoxy and pentafluorophenoxy and, especially preferably, is chlorine.
[0010]
10. PROCESS FOR THE PREPARATION OF A COMPOUND (a) of dichloropyridazine amine of Formula IVa or a salt, tautomer or N-oxide thereof, or of a compound (b) of dichloropyridazine amine of Formula IVb or a salt thereof, tautomer or N-oxide, or (c) a mixture of (a) and (b)
[0011]
11. PROCESS according to claim 10, characterized in that it additionally comprises the step of preparing the compound of Formula II
[0012]
12. A process according to any one of claims 10 to 11, characterized in that it further comprises the conversion step (a) of the dichloropyridazine amine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) of the dichloropyridazine amine compound of Formula IVb or a salt, tautomer or N-oxide thereof, or (c) the mixture of (a) and (b) in a pyridazine amine compound of Formula V or a salt thereof, tautomer or N-oxide via reaction (a) the dichloropyridazine amine compound of Formula IVa or a salt, tautomer or N-oxide thereof, or (b) the dichloropyridazine amine compound of Formula IVb or a salt, tautomer or N-oxide thereof , or (c) the mixture of (a) and (b) with hydrogen in the presence of a hydrogenation catalyst, wherein R1 is according to claim 10; and wherein the process optionally further comprises the step of converting the pyridazine amine compound of Formula V or a salt, tautomer or N-oxide thereof to a compound of Formula VII or a stereoisomer, salt, tautomer or N-oxide thereof by reacting the pyridazine amine compound of Formula V or a salt, tautomer or N-oxide thereof with a compound of Formula VI or a stereoisomer, salt, tautomer or N-oxide wherein R1 is as defined in claim 10, and where R2, R3, RN and X1 are as defined in any of claims 8 to 9.

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法律状态:
2020-04-28| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-07-07| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 10/05/2016, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201562159392P| true| 2015-05-11|2015-05-11|

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