6-Chloroimidazo[2,1-f]pyridazine

Preparation of 6-chloroimidazo[1, 2-b]pyridazine PREPARATION 1; 3-Bromo-6-chloroimidazo[1, 2-b]pyridazine a) 6-Chloroimidazo[1, 2-o]pyridazineHydrobromic acid (48percent solution in water, 1.8 mL, 15.47 mmol) was added to a solution of 2-bromo-1 , 1-diethoxyethane (1 1.6 mL, 77.1 1 mmol) in water (18 mL) at ambient temperature and the resulting mixture was heated at 110 °C. After 45 minutes, the reaction mixture was cooled and diethyl ether was added. The organic layer was separated, dried over magnesium sulphate and the solvent evaporated to obtain a colorless oil, which was added to a suspension at 0 °C of 6-chloropyridazin-3-amine (5.0 g, 38.60 mmol) in n-butanol (8 mL). The resulting mixture was heated at 130 °C overnight. The solvent was removed under reduced pressure, the residue was taken up in a mixture of ethyl acetate and water and the organic layer was separated. The aqueous layer was treated with solid sodium hydrogencarbonate until a basic pH was reached and extracted several times with ethyl acetate. The organic layers were combined, dried over magnesium sulphate and the solvent removed under reduced pressure. The resulting residue was treated with diisopropyl ether, filtered and dried in vacuo to yield the title compound (4.8 g, 85percent) as a beige solid.LRMS (m/z): 154 (M+1)PREPARATION 1 3-Bromo-6-chloroimidazo[1, 2-b]pyridazine; a) 6-Chloroimidazo[1, 2-b]pyridazine Aqueous hydrobromic acid (1.8 mL of a 48percent solution in water, 15.47 mmol) was added to a solution of 2-bromo-1, 1-diethoxyethane (11.6 mL, 77.11 mmol) in water (18 mL) at room temperature and the resulting mixture was heated at 110 C. After 45 minutes, the reaction mixture was cooled and diethyl ether was added. The organic layer was separated, dried over magnesium sulphate and evaporated to obtain a colorless oil, which was added to a suspension at 0 C of 6-chloropyridazin-3-amine (5.0 g, 38.60 mmol) in n-butanol (8 mL). The resulting mixture was heated at 130 C overnight. The solvent was removed under reduced pressure, the residue was taken up in a mixture of ethyl acetate and water and the organic layer was separated. The aqueous layer was treated with solid sodium hydrogencarbonate until a basic pH was reached and extracted several times with ethyl acetate. The organic layers were combined, dried over magnesium sulphate and the solvent removed under reduced pressure. The resulting residue was treated with diisopropyl ether, filtered and dried in vacuo to yield the title compound (4.8 g, 85percent) as a beige solid. LRMS (m/z): 154 (M+1)-1 Synthesis of 6-chloro-imidazo[1, 2-b]pyridazine Chloroacetaldehyde (9.2 mL, 50percent in HTo 6-chloropyridazin-3-amine (19.3 g, 0.149 mol) in 1-butanol (150 mL) was added 26.0 mL of chloroacetaldehyde (7.0 M in water, 1.2 equiv.). The reaction was refluxed overnight and then cooled with an ice bath and the solids were filtered. The solids were washed with small amounts of cold 1-butanol and then Et6-Chloroimidazo[1, 2-b]pyridazine 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 ml (40 mmol) of chloracetaldehyde (55percent strength in water) in 15 ml of n-butanol at 120° C. for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid.5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloracetaldehyde (55percent strength in water) in 15 mL of n-butanol at 1 20 ° C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid. 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 ml_ (40 mmol) of chloracetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120°C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid. 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloracetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120° C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid. 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloroacetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120°C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid. 3-Bromo-6-chloro-imidazo[1 , 2-b]pyridazine was synthesised as example in WO 2007/147646 or DE 10 2006 029447, e.g. as follows Step 1 : Preparation of 6-Chloroimidazo[1 , 2-b]pyridazine : 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloracetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120°C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid. 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloroacetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120° C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with brine and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloroacetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120°C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid.Step 1: 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloroacetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120 C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid.Step 1 : Preparation of 6-Chloroimidazo[1 , 2-b]pyridazine :5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloracetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120°C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid.Step 1: Preparation of 6-Chloroimidazo[1, 2-b]pyridazine (0527) (0528) 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloroacetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120° C. for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid. (0529) To a solution of 2-chloroacetaldehyde (55.1 g, 386 mmol) was added 6- chloropyridazin-3-amine (5 g, 38.6 mmol) and heated to 100 °C for 5 hrs. The reactionmixture was concentrated, suspended in water and extracted with ethyl acetate. Theaqueous layer was neutralized using NaHCO3 solution and the resulting solid was filteredand washed with cold water to afford after drying 6-chloroimidazo[1, 2-bjpyridazine (3 g, 51percent) as pale brown solid. LCMS [m/z 153.9 (M+H)j ‘H NMR (300 MHz, DMSO-d6) ö8.36 (s, 1 H) 8.19-8.27 (m, 1 H) 7.85 (d, J=1.13 Hz, 1 H) 7.37 (d, J9.44 Hz, 1 H).A mixture of A-19 (4.00 g, 30.88 mmol) and 2-chloroacetaldehyde(6.67 g, 33.97 mmol, 5.46 mL, 40percent purity) in n-BuOH (100.0 mL) was stirred at 110 °C for 16hours. The mixture was concentrated to a residue, which was purified by silica gel (PE:EtOAc =1:1 to EtOAc) to afford A-20 (2.00 g, 13.02 mmol) as a solid. ‘H NMR (400 MHz, CDC13) ö117.98 - 7.86 (m, 2H), 7.79 (d, 1H), 7.05 (d, 1H).A solution of 6-chloro-1, 2-diazinan-3-amine (10 g, 73.75 mmol, l.OOequiv), 2-bromo-1, 1-dimethoxyethane (50 g, 295.83 mmol, 4.01 equiv), and HBr(40percent, 45 mL) in ethanol (100 mL) was stirred overnight at 90 °C. The majority of the ethanol was removed under reduced pressure then the pH value of the solution was adjusted to 10 with 5percent aqueous potassium carbonate solution. The resulting mixture was extracted with 6x500 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1/2-1/1) to give 6, 5 g (57percent) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1 H), 7.91 (s, 1H), 7.80 (s, 1 H), 7.05 (d, .7 = 9.3 Hz, 1 H).A solution of 6-chloro-1, 2- diazinan-3-amine (10 g, 73.75 mmol, l.OOequiv), 2-bromo-l, l-dimethoxyethane (50 g, 295.83 mmol, 4.01 equiv), and HBr(40percent, 45 mL) in ethanol (100 mL) was stirred overnight at 90 °C. The majority of the ethanol was removed under reduced pressure then the pH value of the solution was adjusted to 10 with 5percent aqueous potassium carbonate solution. The resulting mixture was extracted with 6x500 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 /2-1 /1) to give 6, 5 g (57percent) of the title compound as a yellow solid. NMR (300 MHz, CDCl3 ) δ 7.95 (s, 1 H), 7.91 (s, 1 H), 7.80 (s, 1 H), 7.05 (d, .7 = 9.3 Hz, 1 H).A solution of 6-chloro-1, 2-diazinan-3-amine (10 g, 73.75 mmol, l.OOequiv), 2-bromo-1, 1-dimethoxyethane (50 g, 295.83 mmol, 4.01 equiv), and HBr(40percent, 45 mL) in ethanol (100 mL) was stirred overnight at 90 °C. The majority of the ethanol was removed under reduced pressure then the pH value of the solution was adjusted to 10 with 5percent aqueous potassium carbonate solution. The resulting mixture was extracted with 6x500 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1/2-1/1) to give 6, 5 g (57percent) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1 H), 7.91 (s, 1H), 7.80 (s, 1 H), 7.05 (d, .7 = 9.3 Hz, 1 H).Intermediate 7: Imidazori, 2-b1pyridazine-6-carboxyiic acid [0199] Step 1. 6-Chloro-imidazori, 2-b1pyridazine. A solution of 6-chloro-l, 2-diazinan-3- amine (10 g, 73.75 mmol, 1.00 equiv), 2-bromo-l, l-dimethoxyethane (50 g, 295.83 mmol, 4.01 equiv), and HBr (40percent, 45 mL) in ethanol (100 mL) was stirred overnight at 90 °C. The majority of the ethanol was removed under reduced pressure then the pH value of the solution was adjusted to 10 with 5percent aqueous potassium carbonate solution. The resulting mixture was extracted with 6x500 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1/2-1/1) to give 6.5 g (57percent) of the title compound as a yellow solid. 1H NMR (300 MHz, CDC1Synthesis of 6-Chloroimidazo[l, 2-b]pyridazine [0516] A mixture of 2-bromo-l, l-dimethoxy ethane (45.67 mg, 0.27 mmol) and 48percent of aqueous HBr (9 mL) was heated up to 120 °C and stirred for 30 min under inert atmosphere. The reaction mixture was cooled to 0° C, NaHC0Sodium acetate (11.01 g, 134 mmol) and concentrated HCl (4.08 mL, 134 mmol) were added successively to a stirred solution of 3-amino-6-chloropyridazine (10 g, 67.1 mmol) and 2-chloro-1, 1-dimethoxyethane(16.72 g, 134 mmol) in 100 mL of 60percent aqueous ethanol. After being stirred resulting reaction mixture at 80 – 85 °C for 16 h, cooled reaction mixture and concentrated ethanol under reduced pressure. Resulting residue was diluted with cold water, the pH was adjusted to 7 with aqueous sodium bicarbonate solution and then extracted with ethyl acetate (3 x 50 mL). Combined organic layers were washed with water (50 mL), brine (50 mL) and dried organic layers over anhydrous sodium sulphate and filtered. The filtrate was concentrated under reduced pressure to get crude product. Crude product was triturated with 5percent ethyl acetate in Petroleum ether: To obtain the title compound in 87.0percent yield as an off-white solid. [0191] Step 1. 6-Chloro-imidazo [1 , 2-bl pyridazine. A solution of 6-chloro- 1 , 2-diazinan-3- amine (10 g, 73.75 mmol, 1.00 equiv), 2-bromo-1, 1-dimethoxyethane (50 g, 295.83 mmol, 4.01 equiv), and HBr (40percent, 45 mL) in ethanol (100 mL) was stirred overnight at 90 °C. The majority of the ethanol was removed under reduced pressure then the pH value of the solution was adjusted to 10 with 5percent aqueous potassium carbonate solution. The resulting mixture was extracted with 6x500 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1/21/1) to give 6.5 g (57percent) of the title compound as a yellow solid. ‘H NMR (300 MHz, CDC13) ö 7.95 (s, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.05 (d, J = 9.3 Hz, 1H).2. 6-Chloro-imidazof1 , 2-blpyridazine (4)[0139] 3-Amino-6-chloro pyridazine (1.5g, 0.0116 mol) was dissolved in n-butanol (12 ml), cooled to O

Molecular Weight:153.57
XLogP3:1.3
Hydrogen Bond Acceptor Count:2
Exact Mass:153.0093748
Monoisotopic Mass:153.0093748
Topological Polar Surface Area:30.2
Heavy Atom Count:10
Complexity:130
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes