METHOD FOR PRODUCING 3,6-DISUBSTITUTED IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVE

Abstract

To provide a method for producing a 3,6-disubstituted imidazo[1,2-b]pyridazine derivative.SOLUTION: A crystal of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazine-6-amine adipate having an X-ray diffraction (XRD) pattern substantially as shown in FIG. 1.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a novel method for preparing 3,6-disubstituted imidazo[1,2-b]pyridazine derivatives. [Background technology]

[0002] 3,6-Disubstituted imidazo[1,2-b]pyridazine derivatives are useful as medicines or raw materials for producing them, and are known to be useful in treating tumors (Patent Document 1).

[0003] In Patent Document 1, all 3,6-disubstituted imidazo[1,2-b]pyridazine derivatives are synthesized by starting from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and introducing a substituent at the 6-position using a nucleophilic aromatic substitution reaction, followed by introducing a substituent at the 3-position using a Suzuki-Miyaura coupling reaction (see, for example, Example 21 of Patent Document 1).

[0004] Another known method for synthesizing 3,6-disubstituted imidazo[1,2-b]pyridazine derivatives is to use 6-chloroimidazo[1,2-b]pyridazine as a starting material and introduce an aryl group into the 3-position of the compound by aromatic substitution reaction utilizing palladium-catalyzed CH activation (Non-Patent Document 1).

[0005] The synthesis method of Patent Document 1 has the limitation that a halogen atom is required at the reaction site of the Suzuki-Miyaura coupling reaction on the imidazo[1,2-b]pyridazine ring, while the synthesis method of Non-Patent Document 1 has the drawback of requiring a large amount of palladium catalyst and of only moderate yield when an electron-donating substituent is present on the aryl group to be introduced (Non-Patent Document 1, for example, Table 2, Entry 11). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] WO2013183578 [Non-patent literature]

[0007] [Non-Patent Document 1] Eur.J.Org.Chem.,862-871(2010) Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention provides a method for producing 3,6-disubstituted imidazo[1,2-b]pyridazine derivatives using an aromatic substitution reaction utilizing palladium-catalyzed CH activation, starting from 6-fluoroimidazo[1,2-b]pyridazine, and provides an industrially useful novel method that requires a small amount of palladium catalyst and can introduce aryl groups bearing electron-donating substituents with complex structures in high yields. [Means for solving the problem]

[0009] The present invention relates to the following (1) to (7). (1) Formula (I):

[0010] [ka]

[0011] or a salt thereof; Formula (II):

[0012] [ka]

[0013] (wherein PG represents a protecting group for a nitrogen atom) or a salt thereof in a solvent in the presence of a palladium catalyst and a base, Formula (III):

[0014] [ka]

[0015] (wherein each symbol is as defined above) or a salt thereof. (2) The production method according to (1), wherein PG in the above formulas (II) and (III) is a tert-butoxycarbonyl group. (3) The method according to either (1) or (2), wherein the palladium catalyst is a catalyst consisting of palladium acetate and tris(2-methylphenyl)phosphine. (4) The method according to any one of (1) to (3), wherein the base is potassium carbonate. (5) The method according to any one of (1) to (4), wherein the solvent is diethylene glycol dimethyl ether. (6) Producing a compound represented by formula (III) or a salt thereof by the production method according to any one of (1) to (5), Formula (IV):

[0016] [ka]

[0017] or a salt thereof; and A compound of formula (V):

[0018] [ka]

[0019] A method for producing a compound represented by the formula: (7) A method for producing an adipic acid salt of the compound represented by formula (V), comprising the steps of producing the compound represented by formula (V) by the production method according to (6), and then salifying the compound using adipic acid.

[0020] In the present invention, the term "palladium catalyst" refers to a divalent palladium catalyst or a zero-valent palladium catalyst, such as tris(2-methylphenyl)phosphinepalladium(0). The "palladium catalyst" of the present invention also includes catalysts prepared in a reaction system by reacting a palladium compound such as palladium chloride or palladium acetate with a monodentate phosphine ligand such as triphenylphosphine, tri-t-butylphosphine, or tris(2-methylphenyl)phosphine, or a bidentate phosphine ligand such as 1,1-bis(diphenylphosphino)methane or 1,2-bis(diphenylphosphino)ethane.

[0021] In the present invention, the reaction can be carried out using an extremely small amount of a palladium catalyst. The amount of the palladium catalyst used is preferably 0.5 to 10 mol %, more preferably 1 to 5 mol %, and more preferably 2 mol %, based on the compound of formula (I).

[0022] The nitrogen-protecting group (PG) that can be used in the present invention may be any substituent that reduces the reactivity of the nitrogen atom in electrophilic addition reactions, and may be, for example, those described in Protective Groups in Organic Synthesis (T.W. Green and P.G.M. Butts, John Wiley & Sons, Inc., New York, 1991). Preferred are tert-butoxycarbonyl and benzyloxycarbonyl groups.

[0023] The solvent that can be used in the present invention is any solvent that does not inhibit the aromatic substitution reaction using the CH activation reaction with palladium. For example, toluene, cyclopentylmethyl Examples of the solvent include ethyl ether, 1,4-dioxane, diethylene glycol dimethyl ether, etc. A solvent that is miscible with water is preferred, for example, diethylene glycol dimethyl ether, etc.

[0024] The compound represented by formula (III) and the compound represented by formula (V) of the present invention can be converted into a salt by reacting with an acid.

[0025] Examples of the salt include inorganic acid salts such as hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide, nitrate, perchlorate, sulfate, and phosphate; C1-C6 alkylsulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, and adipate; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate.

[0026] The compound represented by formula (III) or a salt thereof, and the compound represented by formula (V) or a salt thereof of the present invention may incorporate water molecules to become a hydrate when left in the air or recrystallized, and such hydrates are also encompassed by the present invention.

[0027] The compound represented by formula (III) or a salt thereof, and the compound represented by formula (V) or a salt thereof of the present invention may absorb a certain type of solvent and become a solvate when left in a solvent or recrystallized, and such solvates are also encompassed in the present invention.

[0028] That is, the gist of the present invention relates to the following. Item 1 Figure 1 TIFF2025123513000006.tif97170 A crystalline form of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine adipate having an X-ray diffraction (XRD) pattern substantially as shown in Section 2 A method for producing a crystal of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine adipate, comprising: (i) a compound of formula (V) in ethanol, water, or a combination thereof [ka] or a salt thereof with adipic acid to form a first mixture; and (ii) filtering the first mixture to obtain a filtrate and crystals of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine adipate. A method comprising: Section 3 (iii) adding the filtrate from step (ii) to the solution of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine to form a second mixture; (iv) adding water to the second mixture to form a third mixture; (v) adding seed crystals to the third mixture to form a seeded mixture; (vi) cooling the seeded mixture; and (vii) filtering the mixture of step (vi) to obtain crystals of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine adipate. Item 3. The method of item 2, further comprising: Section 4 Item 4. The method according to Item 3, further comprising a step of drying the crystals of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine adipate obtained in step (vii). Section 5 Item 5. The method according to item 4, wherein the drying step is carried out at an external temperature of 40°C. Section 6 Item 6. The method according to item 4 or 5, wherein the drying step is carried out under reduced pressure at an external temperature of 40°C. Section 7 The compound of formula (V) or a salt thereof (i) Formula (III) [ka] (wherein PG represents a protecting group for a nitrogen atom) or a salt thereof with a compound of formula (IV) [ka] or a salt thereof; and (ii) Deprotecting PG on the nitrogen atom Item 3. The method according to Item 2, wherein the compound is produced by the method according to Item 2. Section 8 Item 8. The method according to item 7, wherein the protecting group is tert-butyl carbonate. Section 9 Item 8. The method of item 7, wherein step (i) occurs in a solvent. Item 10 Item 10. The method of item 9, wherein the solvent is dimethyl sulfoxide. Section 11 8. The method of paragraph 7, wherein step (i) occurs at elevated temperature. Section 12 Item 8. The method of item 7, wherein step (i) occurs at 95°C to 99°C. Item 13 Item 8. The method of item 7, wherein step (ii) occurs in a solvent. Section 14 Item 14. The method of item 13, wherein the solvent is ethanol. Section 15 8. The method of paragraph 7, wherein step (ii) occurs at elevated temperatures. Item 16 Item 8. The method of item 7, wherein step (ii) occurs at 65°C to 70°C. Item 17 Item 8. The method of item 7, wherein step (ii) further comprises reacting with an acid. Section 18 Item 8. The method according to item 7, wherein the acid is hydrochloric acid. Section 19 The deprotection step of step (ii) is carried out by reacting a compound represented by formula (V) [ka] or a salt thereof. Section 20 20. The method of claim 19, wherein the salt is a dihydrochloride salt. [Effects of the Invention]

[0029] The present invention provides a method for producing 3,6-disubstituted imidazo[1,2-b]pyridazine derivatives using an aromatic substitution reaction utilizing palladium-catalyzed CH activation, starting from 6-fluoroimidazo[1,2-b]pyridazine, and provides an industrially useful novel method that requires a small amount of palladium catalyst and can introduce aryl groups bearing electron-donating substituents with complex structures in high yields. DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention will now be described. The reaction conditions of the present invention should not be construed as being limited thereto. In the present invention, functional groups of compounds may be protected with appropriate protecting groups. Examples of such functional groups include hydroxyl groups, carboxyl groups, and amino groups. The types of protecting groups and the conditions for introducing and removing these protecting groups can be found, for example, in Protective Groups in Organic Synthesis (T.W. Green and P.G.M. Butts, John Wiley & Sons, Inc., New York, 1991). [Brief explanation of the drawings]

[0031] [Figure 1]1 shows the powder X-ray diffraction pattern of the crystals of compound (6) obtained in Example 7. The vertical axis of the figure shows the diffraction intensity in terms of relative line intensity (counts), and the horizontal axis shows the value of the diffraction angle 2θ. [Example]

[0032] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to these examples.

[0033] The abbreviations used in the examples have the following meanings. g: gram, mL: milliliter, L: liter, MHz: megahertz.

[0034] In the following examples, nuclear magnetic resonance (hereinafter 1 H NMR (400 MHz) spectra were recorded using tetramethylsilane as the standard substance, and chemical shift values ​​were reported as δ values ​​(ppm). Splitting patterns were indicated as s for singlets, d for doublets, dd for double doublets, m for multiplets, and br for broad.

[0035] The powder X-ray diffraction analysis equipment and analysis conditions are as follows: Equipment: Bruker Axs D8 Discover with GADDS CST X-ray source: CuKα λ=1.54 Å Method: Reflection method Tube voltage: 40 kV Tube current: 40 mA Scanning range: 2~42° Scanning speed: 10° / min

[0036] [Example 1] tert-Butyl [(2R)-1-(4-bromophenoxy)propan-2-yl]carbamate (1)

[0037] [ka]

[0038] Under a nitrogen atmosphere, 1-bromo-4-fluorobenzene (100 g, 0.57 mol, 1 equiv.), N-methylpyrrolidone (500 mL), and D-alaninol (51.5 g, 0.69 mol, 1.2 equiv.) were added, and potassium tert-butoxide (96.1 g, 0.86 mol, 1.5 equiv.) was added at a temperature below 40°C. The mixture was stirred at an internal temperature of approximately 65°C for 3 hours, cooled to below 20°C, and then isopropyl acetate (500 mL) and water (1000 mL) were added and stirred. After allowing to stand and separating the mixture, the aqueous layer was extracted twice with isopropyl acetate (500 mL), and all the organic layers were combined. The combined organic layers were washed twice with water (500 mL), and the resulting organic layer was concentrated under reduced pressure to 300 mL. Ethanol (1000 mL) was added, and the mixture was concentrated under reduced pressure to 300 mL. This process was repeated twice. Tetrahydrofuran (200 mL) was added to this solution and cooled to below 5°C. tert-Butyl dicarbonate (162 g, 0.74 mol, 1.3 equiv.) was dissolved in tetrahydrofuran (100 mL) and added dropwise over approximately 2 hours at below 6°C. After stirring at below 5°C for 1 hour, the mixture was warmed to approximately 20°C and stirred overnight. Ethanol (230 mL) was added, and water (800 mL) was added dropwise over 1.5 hours. After stirring at approximately 50°C for at least 1 hour, the mixture was gradually cooled to 25°C and stirred overnight. The precipitated solid was filtered and washed with a mixture of ethanol (230 mL) and water (270 mL). The mixture was dried under vacuum at an external temperature of 40°C to obtain the title compound (1) (170 g).

[0039] [Example 2] 6-Fluoroimidaz[1,2-b]pyridazine methanesulfonate (2)

[0040] [ka]

[0041] Under a nitrogen atmosphere, benzyltriethylammonium chloride (445 g, 1.95 mol, 1 equiv.) and 6-chloroimidazo[1,2-b]pyridazine (300 g, 1.95 mol, 1 equiv.) (available from, for example, Combi-Block) were added to dimethyl sulfoxide (1500 mL) sequentially. Cesium fluoride (534 g, 3.51 mol, 1.8 equiv.) was then added and stirred at an internal temperature of 79-81 °C for 4 hours. The mixture was cooled to room temperature, and toluene (1500 mL) and sodium bicarbonate (48 g, 0.59 mol, 0.3 equiv.) were added, followed by water (1500 mL). Acetonitrile (600 mL) was added and stirred, and the organic and aqueous layers were separated. The aqueous layer was further extracted three times with a mixture of toluene (1500 mL) and acetonitrile (300 mL), and all organic layers were combined. The combined organic layers were concentrated under reduced pressure to a volume of 2400 mL, and activated carbon (30 g) moistened with toluene (150 mL) was added. The mixture was stirred at approximately 25 °C for 1 hour, filtered, and washed with toluene (750 mL). Acetonitrile (900 mL) was added, and methanesulfonic acid (188 g, 1.95 mol, 1 equiv.) was added dropwise over 1 hour at an internal temperature of 22 to 37 °C. The mixture was stirred at 27 to 31 °C for 1.5 hours, after which the precipitated solid was filtered and washed with toluene (900 mL). The mixture was dried under reduced pressure at an external temperature of 40 °C for 5 hours to obtain the title compound (2) (396.9 g).

[0042] [Example 3] tert-Butyl {(2R)-1-[4-(6-fluoroimidazo[1,2-b]pyridazin-3-yl)phenoxy]propan-2-yl}carbamate (3)

[0043] [ka]

[0044] Under a nitrogen atmosphere, methyl tert-butyl ether (12 L), water (2.6 L), potassium carbonate (691 g, 5.0 mol, 1.1 equiv.), and the compound of formula (2) (1.17 kg, 5.0 mol, 1.1 equiv.) were added sequentially. The mixture was stirred at an internal temperature of 19°C for 5 minutes and allowed to stand, after which the aqueous layer was discarded. The resulting organic layer was concentrated under reduced pressure to adjust the liquid volume to (7.5 L). Diethylene glycol dimethyl ether (7.5 L) was added, and the mixture was again concentrated under reduced pressure to adjust the liquid volume to (8.25 L). To this solution, the compound of formula (1) (1.5 kg, 4.54 mol, 1 equiv.), tris(2-methylphenyl)phosphine (27.7 g, 0.09 mol, 0.02 equiv.), potassium carbonate (1.26 kg, 9.12 mol), and palladium acetate (20.4 g, 0.09 mol, 0.02 equiv.) were sequentially added, followed by washing in with diethylene glycol dimethyl ether (0.3 L). The mixture was stirred at an internal temperature of 95-108°C for 9 hours, followed by stirring at an internal temperature of 58-61°C for 11 hours. Purified water (7.5 L) was added, and the mixture was heated to an internal temperature of 71°C. The aqueous layer was then discarded. 1-Methylimidazole (1.5 L) was added to the organic layer, followed by cooling. After stirring for 40 minutes at 25-30°C, water (9 L) was added intermittently over 1.5 hours at an internal temperature of 25-29°C. After stirring for 19 hours at around 25°C, the crystals were filtered and washed with a mixture of diethylene glycol dimethyl ether (3 L) and water (3 L) and with water (3 L). The solid was dried under reduced pressure at an external temperature of 40°C to obtain the title compound (3) (1.65 kg, 94.1% (gross weight)). 1 H NMR(500 MHz, CDCl3): δ=1.32 (d, J=7.0 Hz, 3 H), 1.47 (s, 9 H), 4.00 (d, J=4.0 Hz, 2 H), 4.10 (brs, 1H), 4.80 (brs, 1H), 6.87 (d, J=7.6 Hz, 1H), 7.02-7.08 (m, 2H), 7.92-7.97 (m, 2H), 8.00 (s, 1H), 8.06 (dd, J=7.6, 6.0 Hz, 1H)

[0045] [Example 4] tert-Butyl {(2R)-1-[4-(6-{[(1R)-1-(3-fluorophenyl)ethyl]amino}imidazo[1,2-b]pyridazin-3-yl)phenoxy]propan-2-yl}carbamate hydrochloride (4)

[0046] [ka]

[0047] Under a nitrogen atmosphere, (1R)-1-(3-fluorophenyl)ethanamine (400 g, 2.87 mol, 1 equiv.), trisodium phosphate (471 g, 2.87 mol, 1 equiv.), and the compound of formula (3) (1.22 kg (net weight 1.12 kg), 3.16 mol, 1.1 equiv.) were sequentially added to dimethyl sulfoxide (2.4 L). The mixture was heated and stirred at an internal temperature of 95-99 °C for 55 hours. After cooling, cyclopentyl methyl ether (4 L) and water (8 L) were added at an internal temperature of 24 °C. The mixture was heated to 50 °C, and the aqueous layer was discarded. Water (4 L) was added to the remaining organic layer, and the aqueous layer was discarded again. The resulting organic layer was concentrated under reduced pressure, and the volume was adjusted to 4 L. This solution was filtered using cyclopentyl methyl ether (0.4 L). A 5 / 8 volume of the resulting solution was withdrawn and used in the subsequent reaction. Cyclopentyl methyl ether (0.25 L), tetrahydrofuran (3 L), and water (0.05 L) were added sequentially to the solution, and concentrated hydrochloric acid (74.9 g, 1.15 mol, 0.4 equiv.) was added at an internal temperature of 23 °C. After stirring at 25 °C for 1.5 hours, a mixture of cyclopentyl methyl ether (1.5 L) and tetrahydrofuran (1.5 L) was added. After stirring for an additional 1.5 hours, concentrated hydrochloric acid (112 g, 1.72 mol, 0.6 equiv.) was added in three portions, one hour apart. After stirring at an internal temperature of 25 °C for 18 hours, the precipitated solid was filtered and washed with a mixture of cyclopentyl methyl ether (1.25 L), tetrahydrofuran (1.25 L), and water (0.025 L). The mixture was dried under reduced pressure at an external temperature of 40°C to obtain the title compound (4) (808.0 g).

[0048] [Example 5] 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethylimidazo[1,2-b]pyridazin-6-amine dihydrochloride (5)

[0049] [ka]

[0050] Under a nitrogen atmosphere, the compound of formula (4) (120.0 g) was dissolved in ethanol (1080 mL), and activated carbon (12 g) moistened with ethanol (60 mL) was added. After stirring for 1 hour, the mixture was filtered and washed with ethanol (120 mL). Concentrated hydrochloric acid (43.3 g) was added to the resulting solution, which was then heated and stirred at 65-70 °C for 4 hours. The mixture was cooled to an internal temperature of 20 °C over 2 hours, stirred at that temperature for 1 hour, and then further cooled to 1 °C over 1 hour. After stirring at an internal temperature of -1 to 1 °C for 19.5 hours, the precipitated solid was filtered and washed with a mixture of chilled ethanol (240 mL) and water (6 mL). The mixture was dried under reduced pressure at an external temperature of 40 °C to obtain the title compound (5) (100.5 g).

[0051] [Example 6] 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethylimidazo[1,2-b]pyridazin-6-amine (V) Under a nitrogen atmosphere, the compound of formula (5) (75.5 g, 0.17 mol) was mixed with ethanol (604 mL) and water (604 mL), and then heated to an internal temperature of 50°C to dissolve. At an internal temperature of 50°C, 25% aqueous sodium hydroxide solution (68.1 g) was added over 3 minutes. The mixture was then cooled to an internal temperature of 1°C over 1.5 hours and stirred for 18.5 hours. The precipitated solid was filtered and washed with a mixture of chilled ethanol (151 mL) and water (151 mL). The mixture was dried under reduced pressure at an external temperature of 40°C to obtain the title compound (V) (58.8 g).

[0052] [Example 7] 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethylimidazo[1,2-b]pyridazin-6-amine adipate (6)

[0053] [ka]

[0054] Under a nitrogen atmosphere, ethanol (90 mL) was added to the compound of formula (V) (30.0 g, 1 equiv.), and the mixture was heated to 50 °C to dissolve the compound, followed by filtration. Adipic acid (11.4 g, 1.1 equiv.) was dissolved in a mixture of ethanol (75 mL) and water (75 mL), filtered, and then added to the 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethylimidazo[1,2-b]pyridazin-6-amine solution. Water (54 mL) was added, and 30.0 mg (0.1% by weight) of seed crystals were added at an internal temperature of 27 °C. The mixture was stirred for 18 hours. Water (306 mL) was added over 1.3 hours at an internal temperature of approximately 41 °C, followed by stirring for 2 hours. The mixture was further cooled to an internal temperature of -1 °C over 1.5 hours and stirred for 16.5 hours. The crystals were filtered and washed with a mixture of chilled ethanol (18 mL) and water (42 mL). They were dried under reduced pressure at an external temperature of 40°C to obtain crystals of the title compound (6) (37.2 g). The XRD chart of the obtained crystals is shown in Figure 1. *Crystals will precipitate naturally if the reaction solution is stirred for a long time, but in this case, to shorten the time it takes for crystals to precipitate, crystals that had been obtained in a similar experiment were added as seed crystals.

[0055] [Reference example] tert-Butyl {(2R)-1-[4-(6-chloroimidazo[1,2-b]pyridazin-3-yl)phenoxy]propan-2-yl}carbamate (7)

[0056] [ka]

[0057] When 6-chloroimidazo[1,2-b]pyridazine and the compound of formula (1) were reacted under the conditions described in Non-Patent Document 1 (palladium acetate 0.1 equiv., triphenylphosphine 0.2 equiv., potassium carbonate 2 equiv., toluene 110°C, 24 hours), the conversion of the compound of formula (7) was about 1.4% by HPLC.

[0058] When 6-chloroimidazo[1,2-b]pyridazine was used as a starting material, it was found that the introduction of an aryl group having an electron-donating substituent with a complex structure resulted in a significantly reduced yield, contrary to the facts described in Non-Patent Document 1. In contrast, Example 3, which used 6-fluoroimidazo[1,2-b]pyridazine as a starting material, showed a high reaction rate despite using one-fifth the amount of palladium catalyst used in the Reference Example, demonstrating the excellent effects of the present invention.

[0059] The present invention includes the following aspects. [1] Formula (I): [ka] or a salt thereof; Formula (II): [ka] (wherein PG represents a protecting group for a nitrogen atom) or a salt thereof in a solvent in the presence of a palladium catalyst and a base, Formula (III): [ka] (wherein each symbol is as defined above) or a salt thereof. [2] The production method according to [1], wherein PG in the above formulas (II) and (III) is a tert-butoxycarbonyl group. [3] The method according to either [1] or [2], wherein the palladium catalyst is a catalyst consisting of palladium acetate and tris(2-methylphenyl)phosphine. [4] The method according to any one of [1] to [3], wherein the base is potassium carbonate. [5] The method according to any one of [1] to [4], wherein the solvent is diethylene glycol dimethyl ether. [6] A compound represented by formula (III) or a salt thereof is produced by the production method according to any one of [1] to [5]. Formula (IV): [ka] or a salt thereof; and A compound of formula (V): [ka] A method for producing a compound represented by the formula: [7] A method for producing an adipic acid salt of a compound represented by formula (V), comprising the steps of producing a compound represented by formula (V) using the production method described in [6], and then salifying the compound using adipic acid.

Claims

1. Figure 1 A crystalline form of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine adipate having an X-ray diffraction (XRD) pattern substantially as shown in

2. A method for producing a crystal of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine adipate, comprising: (i) a compound of formula (V) in ethanol, water, or a combination thereof 【Chemical 1】 or a salt thereof with adipic acid to form a first mixture; and (ii) filtering the first mixture to obtain a filtrate and crystals of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine adipate. A method comprising:

3. (iii) adding the filtrate from step (ii) to the solution of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine to form a second mixture; (iv) adding water to the second mixture to form a third mixture; (v) adding seed crystals to the third mixture to form a seeded mixture; (vi) cooling the seeded mixture; and (vii) filtering the mixture of step (vi) to obtain crystals of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine adipate. The method of claim 2 further comprising:

4. 4. The method according to claim 3, further comprising a step of drying the crystals of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine adipate obtained in step (vii).

5. 5. The method of claim 4, wherein the drying step is carried out at an external temperature of 40°C.

6. 6. The method according to claim 4 or 5, wherein the drying step is carried out under reduced pressure at an external temperature of 40°C.

7. The compound of formula (V) or a salt thereof (i) Formula (III) 【Chemistry 2】 (wherein PG represents a protecting group for a nitrogen atom) or a salt thereof with a compound of formula (IV) 【Chemistry 3】 or a salt thereof; and (ii) Deprotecting PG on the nitrogen atom 3. The method of claim 2, wherein the polymer is produced by the method of claim 2.

8. The method of claim 7, wherein the protecting group is tert-butyl carbonate.

9. 8. The method of claim 7, wherein step (i) occurs in a solvent.

10. 10. The method of claim 9, wherein the solvent is dimethyl sulfoxide.

11. 8. The method of claim 7, wherein step (i) occurs at an elevated temperature.

12. 8. The method of claim 7, wherein step (i) occurs at 95°C to 99°C.

13. 8. The method of claim 7, wherein step (ii) occurs in a solvent.

14. 14. The method of claim 13, wherein the solvent is ethanol.

15. 8. The method of claim 7, wherein step (ii) occurs at elevated temperatures.

16. 8. The process of claim 7, wherein step (ii) occurs at 65°C to 70°C.

17. 8. The method of claim 7, wherein step (ii) further comprises reaction with an acid.

18. 8. The method of claim 7, wherein the acid is hydrochloric acid.

19. The deprotection step of step (ii) is carried out by reacting a compound represented by formula (V) 【Chemistry 4】 or a salt thereof.

20. 20. The method of claim 19, wherein the salt is a dihydrochloride salt.

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