Diester compound or salt thereof, production method therefor, and pyridopyridazine compound production method

Abstract

Provided is a diester compound represented by formula (E) or a salt thereof. In formula (E), R1 and R2 each independently represent a hydrogen atom or a hydrocarbon group, each R3 independently represents a hydrocarbon group, and each X independently represents a halogen atom.

Description

Diester compounds or salts thereof and methods for producing the same, and methods for producing pyridopyridazine compounds

[0001] This disclosure relates to diester compounds or salts thereof and methods for producing the same, as well as methods for producing pyridopyridazine compounds.

[0002] Two types of chemiluminescent substrates are most well known: luminol and L-012 (both known compounds). L-012 is known to exhibit higher signal intensity and sensitivity than luminol, but it has low photostability, and its signal intensity decreases when exposed to fluorescent light.

[0003] Patent Document 1 contains the formula

[0004]

[0005] [In the formula, R １ Each of these represents an optionally substituted hydrocarbon group or heterocyclic group, and R ２ R represents a hydroxyl group, thiol group, amino group, or monosubstituted amino group. ２ If it is a monosubstituted amino group, R ２ is R １ They may also form a ring together. R ３ R represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted thiol group, a halogen atom, a heterocyclic group, a nitro group, a cyano group, an optionally esterified or amidated carboxyl group, an azide group, a sulfo group, or an organic sulfonyl group, provided that R １ If it is an aliphatic group, R ３ The following describes an assay method characterized by utilizing the chemiluminescence of a pyridopyridazine derivative or a salt thereof represented by [X is not a hydrogen atom. X represents an oxygen atom or a sulfur atom.]

[0006] Patent Document 1: Patent No. 3167762

[0007] One embodiment of this disclosure aims to solve a novel diester compound or salt thereof and a method for producing the same, as well as a method for producing a pyridopyridazine compound.

[0008] Means for solving the above problem include the following aspects. <1> A diester compound represented by the following formula (E) or a salt thereof.

[0009] In formula (E), R １ and R ２ each independently represent a hydrogen atom or a hydrocarbon group, R ３ each independently represent a hydrocarbon group, and X each independently represent a halogen atom.

[0010] <2> The diester compound or a salt thereof according to <1>, wherein each X is independently a chlorine atom or a bromine atom. <3> A method for producing a diester compound or a salt thereof, comprising the steps of: halogenating a compound represented by the following formula (E1) to obtain a compound represented by the following formula (E2); aminating the compound represented by the above formula (E2) to obtain a compound represented by the following formula (E3); and dihalogenating the compound represented by the above formula (E3) to obtain the diester compound represented by the following formula (E).

[0011] In the formula, R １ and R ２ each independently represent a hydrogen atom or a hydrocarbon group, R ３ each independently represent a hydrocarbon group, and X and Y each independently represent a halogen atom.

[0012] <4> The method for producing a diester compound or a salt thereof according to <3>, wherein each X is independently a chlorine atom or a bromine atom. <5> A method for producing a pyridopyridazine compound, comprising the steps of: performing a cross-coupling reaction with a metal catalyst on a diester compound represented by the following formula (E) to obtain a compound represented by the following formula (E4); and hydrazinating the compound represented by the above formula (E4) to obtain a pyridopyridazine compound represented by the following formula (P).

[0013] In the formula, R １ and R ２ each independently represent a hydrogen atom or a hydrocarbon group, R ３ each independently represent a hydrocarbon group, R ４ represents a hydrocarbon group or a heterocyclic group, R５ each independently represents X or a hydrocarbon group, and each X independently represents a halogen atom.

[0014] <6> The above R ４ is an alkyl group, and the above R ５ is an alkyl group. The method for producing a pyridopyridazine compound according to <5>.

[0015] According to an embodiment of the present disclosure, a novel diester compound or a salt thereof, a method for producing the same, and a method for producing a pyridopyridazine compound are provided.

[0016] Hereinafter, the content of the present disclosure will be described in detail. In the notation of a group (atomic group) in the present specification, a notation that does not specify substituted or unsubstituted includes both those having no substituent and those having a substituent. For example, the term "alkyl group" includes not only an alkyl group having no substituent (unsubstituted alkyl group) but also an alkyl group having a substituent (substituted alkyl group). In the present specification, in chemical formulas, Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, Bu represents a butyl group, Ac represents an acetyl group, Bn represents a benzyl group, and Ph represents a phenyl group, respectively. In the present specification, the term "step" includes not only an independent step but also a case where the step cannot be clearly distinguished from other steps, as long as the intended effect of the step is achieved. Furthermore, in the present disclosure, a combination of two or more preferred embodiments is a more preferred embodiment.

[0017] (Diester Compound or Salt Thereof) The diester compound or salt thereof according to the present disclosure is a diester compound represented by the following formula (E) or a salt thereof.

[0018] In formula (E), R １ and R ２ each independently represent a hydrogen atom or a hydrocarbon group, R ３ each independently represents a hydrocarbon group, and each X independently represents a halogen atom.

[0019] The diester compounds or salts thereof relating to this disclosure are novel compounds, exhibit excellent synthesis efficiency, and can be synthesized without using reactions such as diazotization, nitration, chlorination, or iron reduction. Furthermore, the diester compounds or salts thereof relating to this disclosure can be suitably used as intermediates in the production of pyridopyridazine compounds.

[0020] R in equation (E) １ and R ２ Each of these is preferably independently a hydrogen atom, an alkyl group, or an aryl group, more preferably a hydrogen atom or an alkyl group, and particularly preferably a hydrogen atom.

[0021] R in equation (E) ３ Each of these is preferably an alkyl group or an aryl group, more preferably an alkyl group, even more preferably an alkyl group having 8 or fewer carbon atoms, and particularly preferably an alkyl group having 2 or fewer carbon atoms.

[0022] R １ ~R ３ The alkyl group in is preferably an alkyl group having 1 to 8 carbon atoms. Examples of alkyl groups having 1 to 8 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, and a cyclopropyl group, which may be linear, branched, or have a cyclic structure.

[0023] R １ ~R ３ The aryl group in this compound is preferably an aryl group having 6 to 14 carbon atoms, and examples include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a biphenylyl group, a 2-anthuryl group, and so on.

[0024] R in equation (E) １ ~R ３ The hydrocarbon group in formula (E) may be an alkyl group or an aryl group. １ ~R ３The hydrocarbon group in may have substituents. Examples of substituents include alkyl groups, aryl groups, heterocyclic groups, alkoxy groups, hydroxyl groups, mercapto groups, halogen atoms, cyano groups, sulfo groups, carboxyl groups, nitro groups, hydroxamic acid groups, sulfino groups, acyl groups, alkoxycarbonyl groups, acyloxy groups, acylamino groups, alkoxycarbonylamino groups, sulfonylamino groups, sulfamoyl groups, carbamoyl groups, alkylthio groups, sulfonyl groups, sulfinyl groups, ureido groups, and the like.

[0025] In formula (E), X is preferably, independently, a chlorine atom, a bromine atom, or an iodine atom, and more preferably a chlorine atom or a bromine atom, from the viewpoint of reactivity and stability.

[0026] Furthermore, the compound represented by formula (E) can be converted into a salt of the compound represented by formula (E) by known salt formation methods. The counter anion in the salt is not particularly limited, and any known counter anion can be used. The compound represented by formula (E) can also be purified by known purification methods such as column chromatography, thin-layer chromatography, recrystallization, and reprecipitation.

[0027] There are no particular restrictions on the method for synthesizing the compound represented by formula (E), but it is preferable to synthesize it by the method for producing diester compounds or salts thereof, as described later.

[0028] Specific examples of compounds represented by formula (E) are shown below, but it goes without saying that compounds represented by formula (1) are not limited to the examples below.

[0029]

[0030] (Method for producing a diester compound or a salt thereof) The method for producing a diester compound or a salt thereof according to the present disclosure includes the steps of: halogenating a compound represented by the following formula (E1) to obtain a compound represented by the following formula (E2); aminating the compound represented by the above formula (E2) to obtain a compound represented by the following formula (E3); and dihalogenating the compound represented by the above formula (E3) to obtain a diester compound represented by the following formula (E).

[0031] In the formula, R １ and R ２ Each of these independently represents a hydrogen atom or a hydrocarbon group, and R ３ Each of the following independently represents a hydrocarbon group, and X and Y independently represent a halogen atom.

[0032] R in equations (E1) to (E3) １ ~R ３ And X are R in formula (E) above, respectively. １ ~R ３ And is synonymous with X, and the preferred embodiments are the same. In formula (E2), Y is preferably a chlorine atom, a bromine atom, or an elemental atom, more preferably a chlorine atom or a bromine atom, and particularly preferably a bromine atom, from the viewpoint of reactivity and stability.

[0033] <Monohalogenation Step> The method for producing a diester compound or a salt thereof according to this disclosure includes a step of halogenating the compound represented by formula (E1) above to obtain the compound represented by formula (E2) above (also referred to as the "monohalogenation step"). There are no particular restrictions on the monohalogenation in the monohalogenation step, but it is preferable to perform monohalogenation by a reaction using N-halosuccinimide. In particular, it is preferable to react N-bromosuccinimide with the compound represented by formula (E1) above under acidic conditions. Furthermore, from the viewpoint of improving reactivity, it is even more preferable to include ammonium acetate in the above reaction. There are no particular restrictions on the solvent used in the monohalogenation step, and known solvents can be used. The solvent used can be appropriately selected considering the reaction rate, reactivity, solubility, and polarity. The amount and concentration of each component used in the reaction can be appropriately selected considering the yield, reaction rate, and reactivity. There are also no particular restrictions on the reaction temperature and time, and they can be appropriately selected.

[0034] <Amination Step> The method for producing a diester compound or a salt thereof according to this disclosure includes a step of aminating a compound represented by formula (E2) to obtain a compound represented by formula (E3) ("also referred to as the amination step"). In the amination step, R１ R ２ A substitution reaction of halogen atoms on the aromatic ring using NH may be carried out, but from the viewpoint of yield, it is preferable to include a step of reacting an amine compound having a protecting group with the compound represented by the above formula (E2), and a step of deprotecting the protecting group. 2,4-dimethoxybenzylamine is a preferred example of the amine compound having a protecting group. A preferred deprotection step is deprotection with an acid. Trifluoroacetic acid is a preferred acid. There are no particular restrictions on the solvent used in the amination step, and any known solvent can be used. The solvent used can be appropriately selected considering the reaction rate, reactivity, solubility, and polarity. The amount and concentration of each component used in the reaction can be appropriately selected considering the yield, reaction rate, and reactivity. There are also no particular restrictions on the reaction temperature and time, and they can be appropriately selected.

[0035] <Dihalogenation Step> The method for producing a diester compound or a salt thereof according to this disclosure includes a step of dihalogenating a compound represented by formula (E3) to obtain a diester compound represented by formula (E) (also referred to as the "dihalogenation step"). There are no particular restrictions on the dihalogenation in the dihalogenation step, but it is preferable to dihalogenate by a reaction using N-halosuccinimide (N-halosuccinimide). In particular, it is preferable to react N-halosuccinimide with the compound represented by formula (E3) by irradiation with microwaves. There are no particular restrictions on the solvent used in the dihalogenation step, and known solvents can be used. The solvent used can be appropriately selected considering the reaction rate, reactivity, solubility, and polarity. The amount and concentration of each component used in the reaction can be appropriately selected considering the yield, reaction rate, and reactivity. There are no particular restrictions on the reaction temperature and time, and they can be appropriately selected.

[0036] Furthermore, the method for producing a diester compound or a salt thereof according to this disclosure may include other steps. There are no particular limitations on the other steps, and known steps can be performed, for example, after each step, a purification step such as liquid-liquid separation, column chromatography, thin-layer chromatography, recrystallization, or reprecipitation; a washing step to wash the obtained compound; a drying step to dry the obtained compound; and a step to form a salt of the obtained compound.

[0037] (Method for producing pyridopyridazine compounds) The method for producing pyridopyridazine compounds according to this disclosure includes the steps of: performing a cross-coupling reaction with a metal catalyst on a diester compound represented by the following formula (E) to obtain a compound represented by the following formula (E4); and hydrazinating the compound represented by the above formula (E4) to obtain a pyridopyridazine compound represented by the following formula (P).

[0038] In the formula, R １ and R ２ Each of these independently represents a hydrogen atom or a hydrocarbon group, and R ３ Each of these independently represents a hydrocarbon group, R ４ R represents a hydrocarbon group or a heterocyclic group. ５ X represents either X or a hydrocarbon group, and each X independently represents a halogen atom.

[0039] R in equations (E4) and (P) １ ~R ３ These are R in the above formula (E), respectively. １ ~R ３ This is synonymous with the same as the preferred embodiment. R in formulas (E4) and (P) ４ R in formulas (E4) and (P) is preferably a hydrocarbon group, more preferably an alkyl group, even more preferably an alkyl group having 8 or fewer carbon atoms, particularly preferably an alkyl group having 2 or fewer carbon atoms, and most preferably a methyl group. ５It is preferably a hydrocarbon group, more preferably an alkyl group, even more preferably an alkyl group having 8 or fewer carbon atoms, particularly preferably an alkyl group having 2 or fewer carbon atoms, and most preferably a methyl group. Also, R in formulas (E4) and (P) ４ and R ５ From the viewpoint of ease of synthesis, it is preferable that these are the same group.

[0040] Preferred embodiments of the hydrocarbon group include those described above. Examples of heterocyclic groups include monocyclic or bicyclic or multicyclic heterocyclic groups containing one or more atoms selected from oxygen, nitrogen, and sulfur atoms as heteroatoms, such as pyridyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, oxazolyl, pyrimidyl, isoxazolyl, triazolyl, furanyl, thiophenyl, and pyrrole groups.

[0041] R in equations (E4) and (P) ４ and R ５ The hydrocarbon group in formula (E4) and formula (P) may be an alkyl group or an aryl group. ４ hydrocarbon groups and heterocyclic groups in, and R ５ The hydrocarbon group in may have substituents. Examples of substituents include R of formula (E). １ ~R ３ The substituents mentioned above are examples of substituents.

[0042] <Cross-Coupling Step> The method for producing a pyridopyridazine compound according to this disclosure includes a step of performing a cross-coupling reaction with a metal catalyst on a diester compound represented by formula (E) above to obtain a compound represented by formula (E4) above (also referred to as the "cross-coupling step"). The cross-coupling reaction in the cross-coupling step is not particularly limited, and known cross-coupling reactions can be performed. Among these, the Suzuki coupling reaction is preferred. In addition, a boronic acid or boron derivative having the group to be introduced can be used in the above reaction, but it is preferable to use a boronic acid having the group to be introduced. Furthermore, a transition metal catalyst is preferred as the metal catalyst, and a palladium catalyst is more preferred. In addition, in the cross-coupling step, it is particularly preferable to perform a Suzuki coupling reaction irradiated with microwaves. The solvent used in the cross-coupling step is not particularly limited, and known solvents can be used. The solvent used can be appropriately selected considering the reaction rate, reactivity, solubility, and polarity. The amount and concentration of each component used in the reaction can be appropriately selected considering the yield, reaction rate, and reactivity. The reaction temperature and time are also not particularly limited and can be appropriately selected.

[0043] <Hydrazine step> The method for producing a pyridopyridazine compound according to this disclosure includes a step of hydrazine the compound represented by formula (E4) to obtain a pyridopyridazine compound represented by formula (P) (also referred to as the "hydrazine step"). The hydrazine reaction in the hydrazine step is not particularly limited, and known hydrazine reactions can be carried out. In particular, it is preferable to carry out a hydrazine reaction using hydrazine and irradiation with microwaves. The solvent used in the hydrazine step is not particularly limited, and known solvents can be used. The solvent used can be appropriately selected considering the reaction rate, reactivity, solubility, and polarity. The amount and concentration of each component used in the reaction can be appropriately selected considering the yield, reaction rate, and reactivity. The reaction temperature and time are also not particularly limited and can be appropriately selected.

[0044] Furthermore, the method for producing pyridopyridazine compounds according to this disclosure may include other steps. There are no particular limitations on the other steps, and known steps can be performed, for example, after each step, a purification step such as liquid-liquid separation, column chromatography, thin-layer chromatography, recrystallization, or reprecipitation; a washing step to wash the obtained compound; a drying step to dry the obtained compound; or a step to form a salt of the obtained compound.

[0045] The present disclosure will be described in detail below with reference to examples, but the disclosure is not limited to these examples. In these examples, "%" and "parts" mean "mass%" and "parts by mass," respectively, unless otherwise specified.

[0046] Purification by silica gel column chromatography was performed using the ISOLERA automated purification system (Biotage). For normal-phase chromatography, CHROMATOREX Q-PACK (Fuji Silicia Co., Ltd.) was used as the support. For reverse-phase chromatography, Sfar C18 (Biotage) was used as the support. Mass (MS) spectra were measured using the ACQUITY SQD LC / MS System (Waters Corporation) and the ionization method: ESI (ElectroSpray Ionization). Retention time (RT) was measured using SQD (Waters Corporation) and expressed in minutes (min). Column: Waters BEH C18 1.7 μm, 2.1 x 30 mm Solvent: Solution A: 0.1% formic acid - water Solution B: 0.1% formic acid - acetonitrile Gradient cycle: 0.00 min (Solution A / Solution B = 95 / 5), 2.00 min (Solution A / Solution B = 5 / 95), 3.00 min (Solution A / Solution B = 95 / 5) Flow rate: 0.5 mL / min Column temperature: 40°C Detection wavelength: 254 nm

[0047] <Synthesis of diethyl 5-bromopyridine-3,4-dicarboxylate>

[0048]

[0049] In a 300 mL three-necked flask, 10 g of diethylpyridine-3,4-dicarboxylate, 100 mL of methanol, 478 μL of sulfuric acid, and 690 mg of ammonium acetate were added, and the mixture was heated to 68°C while stirring. 1.59 g of N-bromosuccinimide was added and the mixture was stirred for 15 minutes. 3.99 g of N-bromosuccinimide was added and the mixture was stirred for 15 minutes. 3.99 g of N-bromosuccinimide was added and the mixture was stirred for 15 minutes. 3.99 g of N-bromosuccinimide was added and the mixture was stirred for 15 minutes. Under ice cooling, potassium carbonate solution was added dropwise to adjust the pH to around 8. After adding ethyl acetate, the organic layer was removed by vacuum distillation, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain diethyl 5-bromopyridine-3,4-dicarboxylate (12 g). Mass spectrometry (MS) (ESI m / z): 302.1 (M+H) Retention time (RT) (min): 1.46

[0050] <Synthesis of Dimethyl 5-Bromopyridine-3,4-Dicarboxylate> The following compounds were obtained in the same manner as in the synthesis of diethyl 5-bromopyridine-3,4-dicarboxylate.

[0051]

[0052] <Synthesis of diethyl 5-[(2,4-dimethoxyphenyl)methylamino]pyridine-3,4-dicarboxylate>

[0053]

[0054] Diethyl 5-bromopyridine-3,4-dicarboxylate (6.65 g), toluene (70 mL), cesium carbonate (14.3 g), 2,4-dimethoxybenzylamine (7.36 g), and 4,5-bis(diphenylphosphin)-9,9-dimethylxanthene (3.82 g) were added to a 100 ml three-necked flask and heated under reflux under a nitrogen atmosphere for 3 hours. After returning to room temperature (25°C, the same applies below), water was added and the organic layer was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain diethyl 5-[(2,4-dimethoxyphenyl)methylamino]pyridine-3,4-dicarboxylate (6.7 g) as an oily substance. MS (ESI m / z): 389.5 (M + H) RT (min): 1.55

[0055] <Synthesis of Dimethyl 5-[(2,4-dimethoxyphenyl)methylamino]pyridine-3,4-dicarboxylate> The following compound was obtained in the same manner as the synthesis of diethyl 5-[(2,4-dimethoxyphenyl)methylamino]pyridine-3,4-dicarboxylate.

[0056]

[0057] <Synthesis of diethyl 5-aminopyridine-3,4-dicarboxylate>

[0058]

[0059] Diethyl 5-[(2,4-dimethoxyphenyl)methylamino]pyridine-3,4-dicarboxylate (6.7 g) was mixed with dichloromethane (40 mL), followed by the addition of trifluoroacetic acid (3.9 mL) under ice cooling. After raising the temperature to room temperature, the mixture was stirred for 4 hours. The reaction mixture was cooled on ice, and sodium bicarbonate solution was added dropwise to adjust the pH to 8. The organic layer was then removed by reduced pressure distillation. The residue was purified by silica gel column chromatography (hexane, ethyl acetate) to obtain diethyl 5-aminopyridine-3,4-dicarboxylate (4.1 g). MS (ESI m / z): 239.4 (M + H) RT (min): 1.00

[0060] <Synthesis of Dimethyl 5-aminopyridine-3,4-dicarboxylate> The following compound was obtained in the same manner as the synthesis of diethyl 5-aminopyridine-3,4-dicarboxylate.

[0061]

[0062] <Synthesis of diethyl 5-amino-2,6-dichloropyridine-3,4-dicarboxylate (a diester compound represented by formula (E))>

[0063]

[0064] Diethyl 5-aminopyridine-3,4-dicarboxylate (1.45 g), acetonitrile (8.0 mL), and N-chlorosuccinimide (2.03 g) were added to a 20 mL microwave reaction vial, and the mixture was irradiated with microwaves and stirred at 50°C for 1 hour. This reaction was repeated four times. Ethyl acetate and sodium bicarbonate solution were added to the collected reaction mixture, and the organic layer was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography to obtain diethyl 5-amino-2,6-dichloropyridine-3,4-dicarboxylate (4.4 g). MS (ESI m / z): 307.3 (M + H) RT (min): 1.51

[0065] <Synthesis of Dimethyl 5-amino-2,6-dichloropyridine-3,4-dicarboxylate (a diester compound represented by formula (E))> The following compound was obtained in the same manner as the synthesis of diethyl 5-amino-2,6-dichloropyridine-3,4-dicarboxylate.

[0066]

[0067] <Synthesis of diethyl 5-amino-2,6-dimethylpyridine-3,4-dicarboxylate, etc.>

[0068]

[0069] Diethyl 5-amino-2,6-dichloropyridine-3,4-dicarboxylate (786 mg), potassium carbonate (1.41 g), 1,1-bis(diphenylphosphino)ferrocenedichloropalladium(II) (374 mg), methylboronic acid (613 mg), tetrahydrofuran (7.86 mL), and water (786 μL) were added to a 20 mL microwave reaction vial. The mixture was then irradiated with microwaves under a nitrogen atmosphere and stirred at 120°C for 4 hours. After treating the reaction mixture with ISOLUTE Si-Thiol, it was purified by silica gel column chromatography to obtain diethyl 5-amino-2,6-dimethylpyridine-3,4-dicarboxylate (205 mg). MS (ESI m / z): 267.4 (M + H) RT (min): 0.90 The same reaction was also carried out using ethylboronic acid or cyclopropylboronic acid instead of methylboronic acid.

[0070]

[0071] <Synthesis of 8-amino-5,7-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyridazine-1-oleate sodium, etc.>

[0072]

[0073] Diethyl 5-amino-2,6-dimethylpyridine-3,4-dicarboxylate (153 mg), methanol (765 μL), and hydrazine (306 μL) were added to a 20 mL microwave reaction vial, and the mixture was irradiated with microwaves and stirred at 100°C for 4 hours. Acetic acid (612 μL) was added, and the mixture was irradiated with microwaves and stirred at 100°C for 1 hour. The precipitated solid was filtered through a Kiriyama funnel, washed twice with a 5% methanol acetate solution, and then washed once with methanol. The obtained solid was dried under reduced pressure to obtain 8-amino-5,7-dimethyl-2,3-dihydropyrido[3,4-d]pyridazine-1,4-dione (105 mg). MS (ESI m / z): 207.3 (M + H) RT (min): 0.30 In addition, the same reaction was carried out using diethyl 5-amino-2,6-diethylpyridine-3,4-dicarboxylate or diethyl 5-amino-2,6-dicyclopropylpyridine-3,4-dicarboxylate instead of diethyl 5-amino-2,6-dimethylpyridine-3,4-dicarboxylate.

[0074]

[0075] <Synthesis of dimethyl 5-amino-2-chloro-6-phenylpyridine-3,4-dicarboxylate (compound represented by formula (P))>

[0076]

[0077] Dimethyl 5-amino-2,6-dichloropyridine-3,4-dicarboxylate (150 mg), sodium carbonate (114 mg), tetrakis(triphenylphosphine)palladium (0) (31 mg), phenylboronic acid (65.5 mg), toluene (900 μL), water (300 μL), and ethanol (300 μL) were added to a 2 mL microwave reaction vial. The mixture was then irradiated with microwaves under a nitrogen atmosphere and stirred at 110°C for 20 minutes. The reaction solution was purified by silica gel column chromatography (ethyl acetate, hexane) to obtain dimethyl 5-amino-2-chloro-6-phenylpyridine-3,4-dicarboxylate (115 mg). MS (ESI m / z): 321.2 (M + H) RT (min): 1.44

[0078] <Synthesis of dimethyl 5-amino-2-chloro-6-(4-methoxyphenyl)pyridine-3,4-dicarboxylate (compound represented by formula (P)), etc.> The following compounds were obtained in the same manner as the synthesis of dimethyl 5-amino-2-chloro-6-phenylpyridine-3,4-dicarboxylate.

[0079]

[0080] <Synthesis of 8-amino-5-chloro-7-phenyl-2,3-dihydropyrido[3,4-d]pyridazine-1,4-dione>

[0081]

[0082] Dimethyl 5-amino-2-chloro-6-phenylpyridine-3,4-dicarboxylate (90 mg), methanol (810 μL), and hydrazine monohydrate (90 μL) were added to a 20 mL microwave reaction vial. The mixture was then microwaved and stirred at 80°C for 1 hour. Acetic acid (315 μL) was added under ice cooling, followed by microwave irradiation and stirring at 120°C for 2 hours. The precipitated solid was filtered and washed with acetate buffer and water. The resulting solid was dried under reduced pressure to obtain 8-amino-5-chloro-7-phenyl-2,3-dihydropyrido[3,4-d]pyridazine-1,4-dione (72 mg). MS (ESI m / z): 289.3 (M+H) RT (min): 1.00

[0083] <Synthesis of 8-amino-5-chloro-7-(4-methoxyphenyl)-2,3-dihydropyrido[3,4-d]pyridazine-1,4-dione, etc.> The compounds shown in the table below were synthesized by the same method as for 8-amino-5-chloro-7-phenyl-2,3-dihydropyrido[3,4-d]pyridazine-1,4-dione.

[0084]

[0085] <Synthesis of diethyl 5-amino-2-chloro-6-(2,6-dimethoxyphenyl)pyridine-3,4-dicarboxylate>

[0086]

[0087] Diethyl 5-amino-2,6-dichloropyridine-3,4-dicarboxylate (4.0 g), tripotassium phosphate (11.1 g), Sphos Pd G3 (4.0 g), 2,6-dimethoxyphenylboronic acid (2.61 g), and toluene (56 mL) were added to a 300 mL three-necked flask, and the mixture was stirred at 130 °C under a nitrogen atmosphere for 3 hours. The reaction mixture was treated with ISOLUTE Si-Thiol to remove residual palladium, and the insoluble matter was filtered off. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain diethyl 5-amino-2-chloro-6-(2,6-dimethoxyphenyl)pyridine-3,4-dicarboxylate (2.0 g). MS (ESI m / z): 409.1 (M + H) RT (min): 1.54

[0088] <Synthesis of diethyl 5-amino-2-chloro-6-(2,4-dimethylthiophen-3-yl)pyridine-3,4-dicarboxylate, etc.> The following compounds were synthesized in the same manner as the synthesis of diethyl 5-amino-2-chloro-6-(2,6-dimethoxyphenyl)pyridine-3,4-dicarboxylate.

[0089]

[0090] <Synthesis of diethyl 5-amino-6-(2,6-dimethoxyphenyl)-2-methylpyridine-3,4-dicarboxylate>

[0091]

[0092] Diethyl 5-amino-2-chloro-6-(2,6-dimethoxyphenyl)pyridine-3,4-dicarboxylate (2.0 g), tripotassium phosphate (4.1 g), Sphos Pd G3 (0.76 g), methylboronic acid (0.88 g), and toluene (28 mL) were added to a 300 mL three-necked flask, and the mixture was stirred at 115°C for 1 hour under a nitrogen atmosphere. The reaction mixture was treated with ISOLUTE Si-Thiol to remove residual palladium, and the insoluble matter was filtered off. The resulting residue was purified by silica gel column chromatography to obtain diethyl 5-amino-6-(2,6-dimethoxyphenyl)-2-methylpyridine-3,4-dicarboxylate (1.74 g). MS (ESI m / z): 389.4 (M + H) RT (min): 1.31

[0093] <Synthesis of diethyl 5-amino-2-chloro-6-(2,4-dimethylthiophen-3-yl)pyridine-3,4-dicarboxylate, etc.> The following compounds were synthesized in the same manner as the synthesis of diethyl 5-amino-6-(2,6-dimethoxyphenyl)-2-methylpyridine-3,4-dicarboxylate.

[0094]

[0095] <Synthesis of 8-amino-7-(2,6-dimethoxyphenyl)-5-methyl-2,3-dihydropyrido[3,4-d]pyridazine-1,4-dione, etc.> The following compounds were synthesized in the same manner as the synthesis of 8-amino-5,7-dimethyl-2,3-dihydropyrido[3,4-d]pyridazine-1,4-dione.

[0096]

[0097] The disclosure of Japanese Patent Application No. 2025-050776, filed on 25 March 2025, is incorporated herein by reference in its entirety. All documents, patent applications, and technical standards described herein are incorporated herein by reference to the same extent as if each individual document, patent application, and technical standard were specifically and individually noted to be incorporated by reference.

Claims

1. A diester compound represented by the following formula (E) or a salt thereof. In formula (E), R １ and R ２ Each of these independently represents a hydrogen atom or a hydrocarbon group, and R ３ Each of the symbols independently represents a hydrocarbon group, and each of the X symbols independently represents a halogen atom.

2. The diester compound or salt thereof according to claim 1, wherein each of the X atoms is independently a chlorine atom or a bromine atom.

3. A method for producing a diester compound or a salt thereof, comprising the steps of: halogenating a compound represented by the following formula (E1) to obtain a compound represented by the following formula (E2); aminating the compound represented by formula (E2) to obtain a compound represented by the following formula (E3); and dihalogenating the compound represented by formula (E3) to obtain a diester compound represented by the following formula (E). In the formula, R １ and R ２ Each of these independently represents a hydrogen atom or a hydrocarbon group, and R ３ Each of the following independently represents a hydrocarbon group, and X and Y independently represent a halogen atom.

4. A method for producing a diester compound or a salt thereof according to claim 3, wherein each of the X atoms is independently a chlorine atom or a bromine atom.

5. A process for producing a pyridopyridazine compound represented by the following formula (P), which comprises a step of subjecting a diester compound represented by the following formula (E) to a cross-coupling reaction using a metal catalyst to obtain a compound represented by the following formula (E4), and a step of reacting the compound represented by the formula (E4) with hydrazine to obtain the pyridopyridazine compound represented by the following formula (P). In the formulae, R １ and R ２ each independently represent a hydrogen atom or a hydrocarbon group, R ３ each independently represent a hydrocarbon group, R ４ represents a hydrocarbon group or a heterocyclic group, R ５ represents X or a hydrocarbon group, and each X independently represents a halogen atom.

6. The aforementioned R ４ However, it is an alkyl group, and the R ５ A method for producing a pyridopyridazine compound according to claim 5, wherein the alkyl group is an alkyl group.

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