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

Abstract

This disclosure relates to a crystal of 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl]imidazo[1,2-b]pyridazin-6-amine adipate.

Claims

1. A crystal 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 that comprises diffraction peaks having the following diffraction angle 20 values: about 6°, about 18.5°, about 19.5°, about 21°.

2. The crystal of claim 1, wherein the XRD pattern further comprises diffraction peaks having the following diffraction angle 20 values: about 9.7°, about 11.8°, and about 13.8°.

3. The crystal of claim 1, wherein the XRD pattern further comprises diffraction peaks having the following diffraction angle 20 values: about 22.5°, about 23.3°, and about 28.8°.

4. A crystal 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 pattern substantially as depicted in FIG. 1.

Description

BRIEF DESCRIPTION OF DRAWING

[0037] FIG. 1 shows a powder X-ray diffraction pattern of the crystals of compound (6) obtained in Example 7. The vertical axis indicates the diffraction intensity as a relative line intensity (counts), and the horizontal axis indicates values of the diffraction angle 20.

EXAMPLES

[0038] Hereinafter, the present invention will be described in more detail with reference to the following Examples. However, these Examples are not intended to limit the scope of the present invention.

[0039] It is to be noted that abbreviations used in the Examples have the following meanings. [0040] g: gram, mL: milliliter, L: liter, MHz: megahertz.

[0041] In the following Examples, with regard to the nuclear magnetic resonance (hereinafter referred to as .sup.1H NMR: 400 MHz) spectrum, the chemical shift value was provided as a δ value (ppm), using tetramethylsilane as a standard substance. For the splitting pattern, the following symbols were used: s, singlet; d, doublet; dd, double doublet; m, multiplet; and br, broad.

[0042] In addition, the powder X-ray diffraction analysis apparatus and analysis conditions were as follows. [0043] Apparatus: D8 Discover with GADDS CST, manufactured by Bruker Axs [0044] X-ray source: CuKαλ=1.54 angstroms [0045] Method: reflection method [0046] Tube voltage: 40 kV [0047] Tube current: 40 mA [0048] Scanning range: 2° to 42° [0049] Scanning rate: 10°/min

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

[0050] ##STR00006##

[0051] Under the 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 then potassium tert-butoxide (96.1 g, 0.86 mol, 1.5 equiv.) was added thereto at 40° C. or less. The resulting mixture was stirred at an internal temperature of about 65° C. for 3 hours and cooled to 20° C. or less. After that, isopropyl acetate (500 mL) and water (1000 mL) were added thereto, and the resulting mixture was stirred. After standing and separating, the aqueous layer was extracted twice with isopropyl acetate (500 mL), and all the organic layers were combined. The combined organic layer was washed twice with water (500 mL), and the obtained organic layer was concentrated under reduced pressure to 300 mL. The operation of further adding ethanol (1000 mL) thereto and concentrating the obtained mixture under reduced pressure to 300 mL was repeated twice. To this solution, tetrahydrofuran (200 mL) was added, and the resulting mixture was cooled to 5° C. or less. tert-Butyl dicarbonate (162 g, 0.74 mol, 1.3 equiv.) was dissolved in tetrahydrofuran (100 mL), and the resulting solution was added dropwise to the mixture at 6° C. or less over about 2 hours. The resulting mixture was stirred at 5° C. or less for 1 hour, and then raised to about 20° C. and stirred overnight. Ethanol (230 mL) was added thereto, and then water (800 mL) was added dropwise over 1.5 hours. The resulting mixture was stirred at about 50° C. for 1 or more hours, and then gradually cooled to 25° C., and stirred overnight. The precipitated solid was filtered and washed with a mixed solution of ethanol (230 mL) and water (270 mL). The solid was dried under vacuum at an external temperature of 40° C. to obtain the title compound (1) (170 g).

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

[0052] ##STR00007##

[0053] Under the 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 Combi-Block or the like) were successively added to dimethyl sulfoxide (1500 mL). Cesium fluoride (534 g, 3.51 mol, 1.8 equiv.) was further added thereto, and then the resulting mixture was stirred at an internal temperature of 79° C. to 81° C. for 4 hours. The mixture was cooled to room temperature, toluene (1500 mL) and sodium bicarbonate (48 g, 0.59 mol, 0.3 equiv.) were added to the mixture, and then water (1500 mL) was added thereto. Acetonitrile (600 mL) was added to the mixture, the resulting mixture was stirred, and then the organic layer and the aqueous layer were separated. Furthermore, the operation of extracting this aqueous layer with a mixed solution of toluene (1500 mL) and acetonitrile (300 mL) was repeated three times, and all the organic layers were combined. The combined organic layer was concentrated under reduced pressure to adjust the liquid volume to 2400 mL. Activated carbon (30 g) moistened with toluene (150 mL) was added thereto. The resulting mixture was stirred around 25° C. for 1 hour, and then filtered and washed with toluene (750 mL). Acetonitrile (900 mL) was added thereto, and then methanesulfonic acid (188 g, 1.95 mol, 1 equiv.) was added dropwise at an internal temperature of 22° C. to 37° C. over 1 hour. The resulting mixture was stirred at 27° C. to 31° C. for 1.5 hours, and then the precipitated solid was filtered and washed with toluene (900 mL). The solid was dried under reduced pressure at an external temperature of 40° C. for 5 hours to obtain the title compound (2) (396.9 g).

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

[0054] ##STR00008##

[0055] Under the 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 the formula (2) (1.17 kg, 5.0 mol, 1.1 equiv.) were successively added. The resulting mixture was stirred at an internal temperature of 19° C. for 5 minutes and allowed to stand, and then the aqueous layer was discharged. The obtained 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 thereto, and the resulting mixture was concentrated under reduced pressure again to adjust the liquid volume to 8.25 L. To this solution, the compound of the 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 successively added, followed by washing with diethylene glycol dimethyl ether (0.3 L). The resulting mixture was stirred at an internal temperature of 95° C. to 108° C. for 9 hours and then stirred at an internal temperature of 58° C. to 61° C. for 11 hours. Purified water (7.5 L) was added thereto, and the resulting mixture was warmed to an internal temperature of 71° C., and then the aqueous layer was discharged. To the organic layer, 1-methylimidazole (1.5 L) was added, and the resulting mixture was cooled. The mixture was stirred at 25° C. to 30° C. for 40 minutes, and then water (9 L) was intermittently added thereto at an internal temperature of 25° C. to 29° C. over 1.5 hours. The resulting mixture was stirred around 25° C. for 19 hours, and then crystals were filtered and washed with a mixed solution of diethylene glycol dimethyl ether (3 L) and water (3 L) and then with water (3 L). The obtained 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)).

[0056] .sup.1HNMR (500 MHz, CDCl.sub.3): δ=1.32 (d, J=7.0 Hz, 3H), 1.47 (s, 9H), 4.00 (d, J=4.0 Hz, 2H), 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)

[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)

[0057] ##STR00009##

[0058] Under the 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 the formula (3) (1.22 kg (net weight: 1.12 kg), 3.16 mol, 1.1 equiv.) were successively added to dimethyl sulfoxide (2.4 L). This mixed solution was warmed and stirred at an internal temperature of 95° C. to 99° C. for 55 hours. The solution was cooled, and cyclopentyl methyl ether (4 L) and water (8 L) were added thereto at an internal temperature of 24° C. The resulting mixture was warmed to 50° C., and the aqueous layer was discharged. After that, water (4 L) was added to the organic layer remaining, and the aqueous layer was discharged again. The obtained organic layer was concentrated under reduced pressure to adjust the liquid volume to 4 L. The liquid was filtered using cyclopentyl methyl ether (0.4 L).

[0059] A portion of the obtained solution in an amount equal to ⅝ times the amount thereof was taken out thereof and used in the subsequent reaction. To the solution, cyclopentyl methyl ether (0.25 L), tetrahydrofuran (3 L), and water (0.05 L) were successively added, and concentrated hydrochloric acid (74.9 g, 1.15 mol, 0.4 equiv.) was added thereto at an internal temperature of 23° C. The resulting mixture was stirred at 25° C. for 1.5 hours, and then a mixed solution of cyclopentyl methyl ether (1.5 L) and tetrahydrofuran (1.5 L) was added thereto. The resulting mixture was further stirred for 1.5 hours, and then concentrated hydrochloric acid (112 g, 1.72 mol, 0.6 equiv.) was added thereto in three portions every hour. The resulting mixture was stirred at an internal temperature of 25° C. for 18 hours. The precipitated solid was filtered and washed with a mixed solution of cyclopentyl methyl ether (1.25 L), tetrahydrofuran (1.25 L), and water (0.025 L). The solid was dried under reduced pressure at an external temperature of 40° C. to obtain the title compound (4) (808.0 g).

[Example 5] 3-{4-[(2R)-2-Aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl-imidazo[1,2-b]pyridazin-6-amine dihydrochloride (5)

[0060] ##STR00010##

[0061] Under the nitrogen atmosphere, the compound of the formula (4) (120.0 g) was dissolved in ethanol (1080 mL), and then activated carbon (12 g) moistened with ethanol (60 mL) was added thereto. The resulting mixture was stirred for 1 hour, and then filtered and washed with ethanol (120 mL). To the obtained solution, concentrated hydrochloric acid (43.3 g) was added, and the resulting mixture was warmed, and stirred at 65° C. to 70° C. for 4 hours. The mixture was cooled to an internal temperature of 20° C. over 2 hours and stirred at that temperature for 1 hour, and then further cooled to 1° C. over 1 hour. The mixture was stirred at an internal temperature of −1° C. to 1° C. for 19.5 hours. After that, the precipitated solid was filtered and washed with a mixed solution of cold ethanol (240 mL) and water (6 mL). The solid was dried under reduced pressure at an external temperature of 40° C. to obtain the title compound (5) (100.5 g).

[Example 6] 3-{4-[(2R)-2-Aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl-imidazo[1,2-b]pyridazin-6-amine (V)

[0062] Under the nitrogen atmosphere, the compound of the formula (5) (75.5 g, 0.17 mol), ethanol (604 mL), and water (604 mL) were mixed together and then warmed to an internal temperature of 50° C. to dissolve the compound. A 25% sodium hydroxide aqueous solution (68.1 g) was added thereto at an internal temperature of 50° C. for 3 minutes. After that, the resulting mixture was 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 cold mixed solution of ethanol (151 mL) and water (151 mL). The solid was dried under reduced pressure at an external temperature of 40° C. to obtain the title compound (V) (58.8 g).

[Example 7] 3-{4-[(2R)-2-Aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethyl-imidazo[1,2-b]pyridazin-6-amine adipate (6)

[0063] ##STR00011##

[0064] Under the nitrogen atmosphere, ethanol (90 mL) was added to the compound of the formula (V) (30.0 g, 1 equiv.), and the temperature was raised to 50° C. to dissolve the compound, followed by filtration. Adipic acid (11.4 g, 1.1 equiv.) was dissolved in a mixed solution of ethanol (75 mL) and water (75 mL), followed by filtration. The filtrate was added to a 3-{4-[(2R)-2-aminopropoxy]phenyl}-N-[(1R)-1-(3-fluorophenyl)ethylimidazo[1,2-b]pyridazin-6-amine solution. Water (54 mL) was added thereto and 30.0 mg (0.1% by weight) of seed crystals* were added thereto at an internal temperature of 27° C., followed by stirring for 18 hours. Water (306 mL) was added thereto at an internal temperature of about 41° C. over 1.3 hours, and then the resulting mixture was stirred for 2 hours. Furthermore, the mixture was cooled to an internal temperature of −1° C. over 1.5 hours and stirred for 16.5 hours. Crystals were filtered and washed with a cold mixed solution of ethanol (18 mL) and water (42 mL). The crystals were dried under reduced pressure at an external temperature of 40° C. to obtain crystals of the title compound (6) (37.2 g). An XRD chart of the obtained crystals is shown in FIG. 1. Crystals precipitate spontaneously when the reaction solution is stirred for a long period of time. Here, however, in order to reduce the time taken for crystals to precipitate, crystals previously obtained in a similar experiment were added as seed crystals.

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

[0065] ##STR00012##

[0066] 6-Chloroimidazo[1,2-b]pyridazine and the compound of the formula (1) were reacted under the conditions disclosed in Non Patent Literature 1 (palladium acetate, 0.1 equiv.; triphenylphosphine, 0.2 equiv.; potassium carbonate, 2 equiv.; toluene, 110®C; 24 hours). As a result, the reaction rate of the compound of the formula (7) on HPLC was about 1.4%.

[0067] Contrary to the disclosure in Non Patent Literature 1, it was revealed that when 6-chloroimidazo[1,2-b]pyridazine was used as a starting material, the introduction of an aryl group having an electron-donating substituent with a complicated structure causes an extremely large reduction in yield. In contrast, in Example 3 using 6-fluoroimidazo[1,2-b]pyridazine as a starting material, a high reaction rate was exhibited although the amount of the palladium catalyst used was one fifth of that in the Reference Example, and this shows an excellent effect of the present invention.