* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With N-Bromosuccinimide In chloroform at 0 - 20℃; Stage #2: With water; sodium hydrogencarbonate In chloroform; ethyl acetate
3-Bromo-6-chloroimidazo[1,2-b]pyridazine 478 mg (3.11 mmol) of 6-chloroimidazo[1,2-b]pyridazine were introduced into 10 ml of chloroform under argon and, while cooling in ice, 664 mg (3.73 mmol) of N-bromo-succuinimide were added. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction mixture was then mixed with water and ethyl acetate and, after addition of saturated sodium bicarbonate solution, the phases were separated. The aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate. In the final removal of the solvent in vacuo, the desired product was isolated in quantitative yield in the form of an amorphous white solid which was employed without further chromatographic purification in subsequent reactions.1H-NMR (CDCl3, stored over molecular sieves): δ=7.12 (d, 1H); 7.79 (s, 1H); 7.90, (d, 1H) ppm.
100%
With N-Bromosuccinimide In chloroform at 20℃; Inert atmosphere; Cooling with ice
478 mg (3.11 mmol) of 6-chloroimidazo[1 ,2-b]pyridazine were introduced into 10 mL of chloroform under argon and, while cooling in ice, 664 mg (3.73 mmol) of N-bromosuccuinimide were added. After the addition was complete, the reaction mixture was stirred at rt over night. The reaction mixture was then mixed with water and ethyl acetate and, after addition of saturated sodium bicarbonate solution, the phases were separated. The aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate. In the final removal of the solvent in vacuo, the desired product was isolated in quantitative yield in the form of an amorphous white solid which was employed without further chromatographic purification in subsequent reactions. 1H-NMR (CDC , stored over molecular sieves): δ [ppm] (1 H) ppm.
100%
With N-Bromosuccinimide In chloroform at 20℃; Inert atmosphere; Cooling with ice
478 mg (3.1 1 mmol) of 6-chloroimidazo[1 ,2-b]pyridazine were introduced into 10 mL of chloroform under argon and, while cooling in ice, 664 mg (3.73 mmol) of N-bromosuccuinimide were added. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction mixture was then mixed with water and ethyl acetate and, after addition of saturated sodium bicarbonate solution, the phases were separated. The aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate. In the final removal of the solvent in vacuo, the desired product was isolated in quantitative yield in the form of an amorphous white solid which was employed without further chromatographic purification in subsequent reactions. 1H-NMR (CHLOROFORM-d): δ [ppm] = 7.12 (d, 1 H); 7.79 (s, 1 H); 7.90, (d, 1 H).
100%
With N-Bromosuccinimide In chloroform at 20℃; Inert atmosphere
478 mg (3.11 mmol) of 6-chloroimidazo[1 ,2-b]pyridazine were introduced into 10 mL of chloroform under argon and, while cooling in ice, 664 mg (3.73 mmol) of N-bromosuccuinimide were added. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction mixture was then mixed with water and ethyl acetate and, after addition of saturated sodium bicarbonate solution, the phases were separated. The aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate. In the final removal of the solvent in vacuo, the desired product was isolated in quantitative yield in the form of an amorphous white solid which was employed without further chromatographic purification in subsequent reactions. 1H-NMR (CHLOROFORM-d): δ [ppm] = 7.12 (1 H); 7.79 (1 H); 7.90 (1 H).
100%
With N-Bromosuccinimide In chloroform at 0 - 20℃; Inert atmosphere; Cooling with ice
478 mg (3.1 1 mmol) of 6-chloroimidazo[1 ,2-b]pyridazine were introduced into 10 mL of chloroform under argon and, while cooling in ice, 664 mg (3.73 mmol) of N- bromosuccuinimide were added. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction mixture was then mixed with water and ethyl acetate and, after addition of saturated sodium bicarbonate solution, the phases were separated. The aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were then washed with brine and dried over sodium sulfate. In the final removal of the solvent in vacuo, the desired product was isolated in quantitative yield in the form of an amorphous white solid which was employed without further chromatographic purification in subsequent reactions.
100%
With N-Bromosuccinimide In chloroform at 20℃; Inert atmosphere
478 mg (3.11 mmol) of 6-chloroimidazo[l,2-b]pyridazine were introduced into 10 mL of chloroform under argon and, while cooling in ice, 664 mg (3.73 mmol) of /V-bromo- succinimide were added. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction mixture was then mixed with water and ethyl acetate and, after addition of saturated sodium bicarbonate solution, the phases were separated. The aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were then washed with saturated sodium chloride solution and dried over sodium sulfate. In the final removal of the solvent in vacuo, the desired product was isolated in quantitative yield in the form of an amorphous white solid which was employed without further chromatographic purification in subsequent reactions.H-NMR (CHLOROFORM-d): δ [ppm] = 7.12 (d, 1H); 7.79 (s, 1H); 7.90, (d, 1H).
100%
With N-Bromosuccinimide In chloroform at 20℃; Inert atmosphere; Cooling with ice
Step 2: Preparation of 3-Bromo-6-chloroimidazo[1,2-b]pyridazine 478 mg (3.11 mmol) of 6-chloroimidazo[1,2-b]pyridazine were introduced into 10 mL of chloroform under argon and, while cooling in ice, 664 mg (3.73 mmol) of N-bromosuccuinimide were added. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction mixture was then mixed with water and ethyl acetate and, after addition of saturated sodium bicarbonate solution, the phases were separated. The aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate. In the final removal of the solvent in vacuo, the desired product was isolated in quantitative yield in the form of an amorphous white solid which was employed without further chromatographic purification in subsequent reactions. 1H-NMR (CHLOROFORM-d): δ [ppm]=7.12 (1H); 7.79 (1H); 7.90 (1H).
100%
With N-Bromosuccinimide In chloroform at 20℃; Inert atmosphere; Cooling with ice
478 mg (3.1 1 mmol) of 6-chloroimidazo[1 ,2-b]pyridazine were introduced into 10 mL of chloroform under argon and, while cooling in ice, 664 mg (3.73 mmol) of N- bromo-succinimide were added. After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction mixture was then mixed with water and ethyl acetate and, after addition of saturated sodium bicarbonate solution, the phases were separated. The aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were then washed with saturated sodium chloride solution and dried over sodium sulfate. In the final removal of the solvent in vacuo, the desired product was isolated in quantitative yield in the form of an amorphous white solid which was employed without further chromatographic purification in subsequent reactions.1H-NMR (CHLOROFORM-d): δ [ppm] = 7.12 (d, 1 H); 7.79 (s, 1 H); 7.90, (d, 1 H).
100%
With N-Bromosuccinimide In chloroform at 20℃; Inert atmosphere
Step 2: Preparation of 3-Bromo-6-chloroimidazo[1 ,2-b]pyridazine478 mg (3.1 1 mmol) of 6-chloroimidazo[1 ,2-b]pyridazine were introduced into 10 mL of chloroform under argon and, while cooling in ice, 664 mg (3.73 mmol) of N-bromosuccuinimide were added. After the addition was complete, the reaction mixture was stirred at rt over night. The reaction mixture was then mixed with water and ethyl acetate and, after addition of saturated sodium bicarbonate solution, the phases were separated. The aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate. In the final removal of the solvent in vacuo, the desired product was isolated in quantitative yield in the form of an amorphous white solid which was employed without further chromatographic purification in subsequent reactions.1H-NMR (CDCla, stored over molecular sieves): δ [ppm]= 7.12 (1 H); 7.79 (1 H); 7.90, (1 H) ppm.
100%
With N-Bromosuccinimide In chloroform at 0 - 20℃;
A solution of 6-chloro-imidazo[1,2-b]pyridazine (3.4g, 21.9 mmol) in CHCl3 (71 mL) was cooled to 0 °C.N-bromosuccinimide (4.46 g, 26.28 mmol) was added and the mixture was stirredat room temperature during 7 h. 1N NaHCO3 (100 mL) and AcOEt wereadded at 0 °C with stirring. The product was extracted with AcOEt, and theorganic layer was washed with brine. The organic layer was dried over Na2SO4,filtered, and evaporated under reduce pressure to give compound 4 as a yellowish solid in 100 percent yield(5.48 g). Mp = 159-160 °C; Litt31H NMR (DMSO-d6): δ 7.05 (d, 1H, J = 9.2 Hz, H-8pyridazine),7.72 (s, 1H, H-2Imid), 7.83 (d, 1H, J = 9.2 Hz, H-7pyridazine). 13C NMR(DMSO-d6): δ 101.48 (C),119.11 (CH), 127.22 (CH), 134.98 (CH), 138.36 (C), 148.13 (C);HPLC: Rt= 2.17 min.
98%
With N-Bromosuccinimide In chloroform for 4 h; Reflux
6-Chloroimidazo[1,2-b]pyridazine (8.5 g, 0.055 mol) and N-bromosuccinimide (10.0 g, 0.056 mol) were combined in chloroform (250 mL) and refluxed for 4 hours. The reaction was cooled with an ice bath and the solids filtered. The filtrate was diluted with chloroform (150 mL) and saturated Na2CO3 solution (100 mL) and then vigorously stirred for an hour. The organic phase was washed with more saturated Na2CO3 solution and dried over MgSO4. After evaporation, 3-bromo-6-chloro-imidazo[1,2-b]pyridazine was obtained as a tan solid (12.64 g, 98percent).MS (ESI (+)m/z): 233.87 (M+H+)1H NMR (CDCl3-d1, 300 MHz), δ 7.83 (d, J=9.3 Hz, 1H), 7.72 (s, 1H), 7.05 (d, J=9.3 Hz, 1H).
92%
Stage #1: With N-Bromosuccinimide; trifluoroacetic acid In acetonitrile at 20℃; Stage #2: With sodium hydrogencarbonate In ethyl acetate
Intermediate A 3-Bromo-6-chloroimidazo[1 ,2-b]pyridazine intermediate A To a solution of 6-chloroimidazo[1 ,2-b]pyridazine (5 g, 32.6 mmol) in acetonitrile (300 ml) was added 1-bromopyrrolidine-2,5-dione (6.37 g, 35.8 mmol) and trifluoroacetic acid (0.75 mL). The resulting solution was allowed to stirr at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc, washed with NaHCOs solution, water and brine, dried over Na2SO4 and concentrated in vacuo to afford 7.2 g title compound in 92percent yield as a light yellow solid. 1H-NMR (400MHz, CDCI3) δ ppm 7.91 (d, 1 H), 7.79 (s, 1 H), 7.12 (d, 1 H). LCMS (method A): [MH]+ = 232/234, tR = 4.48 min.
92%
at 20℃; for 0.333333 h;
b) 3-Bromo-6-chloroimidazo[1 ,2-b]pyridazine; Bromine (3.8 mL, 74.19 mmol) was added dropwise to a solution of 6-chloroimidazo [1 ,2-b]pyridazine (Preparation 1 a, 4.8 g, 31.06 mmol) in glacial acetic acid (80 mL) and the resulting mixture was stirred at ambient temperature for 20 minutes. The precipitate formed was collected by filtration, washed with diethyl ether several times and dried in vacuo. The solid obtained was partitioned between ethyl acetate and a saturated aqueous solution of potassium carbonate. The organic layer was separated and washed with a saturated aqueous solution of potassium carbonate, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude was then treated with pentane, filtered and the solid obtained was dried in vacuo to yield the title compound (6.6 g, 92percent) as a pale yellow solid.LRMS (m/z): 232 (M+1)+.1H-NMR δ (300 MHz, CDCI3):7.13 (d, 1H), 7.80 (s, 1H), 7.92 (d, 1H).
92%
Stage #1: at 20℃; for 0.333333 h; Stage #2: With potassium carbonate In water; ethyl acetate
b) 3-Bromo-6-chloroimidazo[1,2-b]pyridazine Bromine (3.8 mL, 74.19 mmol) was added dropwise to a solution of 6-chloroimidazo [1,2-b]pyridazine (preparation 1 a, 4.8 g, 31.06 mmol) in glacial acetic acid (80 mL) and the resulting mixture was stirred at room temperature for 20 minutes. The precipitate formed was collected by filtration, washed with diethyl ether several times and dried in vacuo. The solid obtained was partitioned between ethyl acetate and a saturated aqueous solution of potassium carbonate. The organic layer was separated and washed with a saturated aqueous solution of potassium carbonate (x3), dried over magnesium sulphate and the solvent removed under reduced pressure. The crude was then treated with pentane, filtered and the solid obtained was dried in vacuo to yield the title compound (6.6 g, 92percent) as a pale yellow solid. LRMS (m/z): 232 (M+1)+. 1H-NMR δ (300 MHz, CDCl3):7.13 (d, 1H), 7.80 (s, 1H), 7.92 (d, 1H).
86%
Stage #1: With bromine In methanol; acetic acid at 20℃; for 1 h; Stage #2: With sodium hydrogensulfite In methanol; water; acetic acid
Bromine (1.74 mL, 34 mmol) was added dropwise to an ice cold mixture of acetic acid (2 mL) and 6-Chloro-imidazo[1,2-b]pyridazine (6.72 g, 34 mmol) in methanol (300 mL). After the addition was completed the mixture was allowed to warm to room temperature and then stirred for one hour. The reaction was treated with saturated aqueous sodium bisulfite (100 mL) and the volatiles were removed under vacuum followed by the addition of ethyl acetate (150 mL). The solids were collected by filtration and dried under vacuum to give 3-bromo-6-chloro-1-yl-imidazo[1,2-b]pyridazine as a pinkish solid (3.20 g): mp 157° C. The organic layer of the filtrate was dried over anhydrous magnesium sulfate, filtered and evaporated to give a second crop of 3-bromo-6-chloro-1-yl-imidazo[1,2-b]pyridazine as a yellow solid. The combined solids were 6.71 g (86percent).
60%
at 20℃; for 0.333333 h;
3. 3-Bromo-6-chloro-imidazon , 2-blpyridazine (5)[0140] The 6-Chloro-imidazo[1 ,2-b]pyridazine (4) (500 mg, 0.0032 mol) was taken in glacial acetic acid (5 ml) and bromine (0.4 ml) was added slowly at room temperature. After 20 minutes, solid precipitated out and was filtered. The solid was washed with ether (3 x 15 ml) and dried under air to give 3-Bromo-6-chloro-imidazo[1 ,2-b]pyridazine (5) (400mg, yield = 60percent).
20.4 g
With N-Bromosuccinimide In chloroform for 0.666667 h; Reflux; Cooling with ice
Example 15 -2 Synthesis of 3-bromo-6-chloroimadazo[1,2-b]pyridazine 6-Chloroimadazo[1,2-b]pyridazine 1*a (193.5mmol) was dissolved in chloroform (600 ml) and cooled in an ice bath. NBS (1.05 eq) was then added and the reaction mixture warmed to room temperature, then heated to reflux for 40 minutes. The reaction was cooled, concentrated in vacuo and the solid residue dissolved in EtOAc. The organic layer was washed with aq. K2CO3 (x 3), brine, and then dried with MgSO4, filtered and concentrated in vacuo. The product was recrystallised with EtOAc/hexane and triturated with hexane and IPA. Yield (20.4 g) 1H-NMR (250MHz,CDCl3) : δ = 7.11 (1H, d, J 7 Hz, Ar), 7.79 (1H, s, Ar), 7.9 (1H, d, J 8.6Hz, Ar); HPLC: HPLC Rt 1.86 (100percent); m/z (ES+): 233.95 (100percent).
With palladium on activated charcoal; hydrogen; triethylamine In tetrahydrofuran; methanol for 16 h;
To a stirred solution of 6-chloroimidazo[1,2-bjpyridazine (800 mg, 5.21 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL) was added triethylamine (0.8 mL, 5.74mmol) followed by Pd/C (100 mg, 0.094 mmol). The mixture was stirred under hydrogen atmosphere for 16h. The reaction mixture was filtered through celite and the celite bed was washed with methanol. The combined filtrate was concentrated then suspended in water and extracted with ethyl acetate (3x). The organic layer was dried over Na2SO4 and filtered to give the imidazo[1,2-bjpyridazine (550 mg, 87percent) as off white solid. LCMS[m/z 120 (M+H)j; ‘H NMR (300 MHz, DMSO-d6) ö 8.51 (dd, J4.53, 1.51 Hz, 1H) 8.29(d,J0.76Hz, 1 H) 8.05-8.19(m, 1 H)7.79(d,J1.13 Hz, 1 H) 7.22 (dd,J=9.44,4.53 Hz, 1 H).
Stage #1: With hydrogen bromide In isopropyl alcohol for 1.5 h; Reflux Stage #2: for 2 h; Reflux
Preparation of 6-chloroimidazo[1,2-b]pyridazine Bromoacetaldehyde diethylacetal (13.7 g, 69.5 mmol, 1.8 equiv) was added to hydrobromic acid (4.0 mL) and heated to reflux for 1.5 h. The reaction mixture was cooled to rt then poured into a reaction flask containing excess sodium bicarbonate in isopropanol. The solution was stirred for 3 min and then filtered. To the mother liquor was added 3-amino-6-chloropyridazine (5.0 g, 38.6 mmol, 1.0 equiv) and heated to reflux for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. Purification using column chromatography gave 5.1 g of the brown solid, 86percent: 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.88 (d, J=9.3 Hz, 1H), 7.74 (s, 1H), 7.01 (d, J=9.3 Hz, 1H).
85%
Stage #1: With hydrogen bromide In water at 20 - 110℃; for 0.75 h; Stage #2: at 0 - 130℃;
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)+.1H-NMR δ (300 MHz, CDCI3): 7.08 (d, 1 H), 7.81 (s, 1 H), 7.88 - 7.99 (m, 2H).
85%
Stage #1: With hydrogen bromide In water at 110℃; for 0.75 h; Stage #2: at 0 - 130℃;
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)+. 1H-NMR δ (300 MHz, CDCl3): 7.08 (d, 1H), 7.81 (s, 1H), 7.88 -7.99 (m, 2H).
59%
Stage #1: for 1.5 h; Reflux Stage #2: With sodium hydrogencarbonate In isopropyl alcohol for 2 h; Reflux
Example 15 -1 Synthesis of 6-chloro-imidazo[1,2-b]pyridazine A Solution of 48percent HBr (25.2ml) was added to bromoacetaldehyde diethyl acetal (104 g, 0.618 mol) and the resultant mixture was heated to reflux for 1.5 hrs. The reaction mixture was then poured into a suspension of NaHCO3 (20.0 g) in isopropyl alcohol (800 ml). The solution was filtered and 3-amino-6-chloropyridazine (40.0 g, 0.309 mol) was added to the filtrate and the mixture heated at reflux for 2 hours. The mixture was cooled, evaporated to dryness, dissolved in ethyl acetate (1 L), washed with a saturated aqueous solution of NaHCO3 (500 ml), followed by brine (500 ml). The organic layer was then dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution with hexane and ethyl acetate 0 to 100percent) to give 28.0 g (59percent) of 6-chloro-imidazo[1,2-b]pyridazine 1*a as a brown solid. 1H-NMR (400 MHz, DMSO-d6): 8.35 (1H, d, J = 0.9 Hz), 8.23 (1 H, d, J = 9.5 Hz), 7.86 (1 H, d, J = 1.1 Hz), 7.36 (1 H, d, J = 9.5 Hz). LCMS-ESI (m/z); found 154.0 [M+H]+.
Reference：
[1] Patent: US2014/256733, 2014, A1, . Location in patent: Paragraph 0227-0229
[2] Patent: WO2012/69202, 2012, A1, . Location in patent: Page/Page column 46
[3] Patent: EP2463289, 2012, A1, . Location in patent: Page/Page column 17-18
[4] Patent: EP2818471, 2014, A1, . Location in patent: Paragraph 0117; 0118
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2789 - 2798
[6] Journal of Medicinal Chemistry, 2014, vol. 57, # 21, p. 8839 - 8848
[7] MedChemComm, 2018, vol. 9, # 10, p. 1733 - 1745
4
[ 107-20-0 ]
[ 5469-69-2 ]
[ 6775-78-6 ]
Yield
Reaction Conditions
Operation in experiment
92%
at 20℃; for 18 h; Reflux
Chloroacetaldehyde (9.2 mL, 50percent in H2O) wasadded to a solution of 3-amino-6-chloropyridazine (6 g, 46 mmol) in 70 mL n-butanolat room temperature. This mixture was refluxed for 18 h and the then cooled toroom temperature. The resulting precipitate was filtered, washed with butanoland ethyl ether and dissolved in water. NaOH (1N) was added and the extractedwith ethyl acetate and the organic layer was washed with NaHCO3. Theorganic layer was dried over Na2SO4, filtered, andevaporated under reduced pressure to give the compound 1 as a pink amorphous in 92percent yield: Mp 116-118 °C; Litt1 115-117.5°C; 1H NMR (CDCl3):δ 7.35 (d, 1H, J = 9.6 Hz, H-8pyridazine),7.85 (s, 1H, H-2Imid),8.22 (d, 1H, J = 9.6 Hz, H-7pyridazine), 8.34 (s, 1H, H-3Imid). 13CNMR (DMSO-d6): δ117.99 (CH), 119.40 (CH), 128.21 (CH), 134.99 (CH), 137.67 (C), 146.78(C).HPLC: Rt= 1.55 min.
79%
Reflux
To 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 Et2O. 23.6 g of tan solid were recovered and dissolved in water (135 mL). A NaOH solution (1.0 N, 150 mL) was slowly added and copious solids were obtained. AcOEt (150 mL) was added and the aqueous phase was extracted with AcOEt. The organic layer was washed with a saturated solution of NaHCO3 and then dried over MgSO4. After evaporation, 6-chloroimidazo[1,2-b]pyridazine was obtained as a pink solid (18.1 g, 79percent).MS (ESI (+)m/z): 153.38 (M+H+)1H NMR (MeOD-d4, 300 MHz), δ 8.14 (s, 1H), 8.05 (d, J=9.3 Hz, 1H), 7.80 (s, 1H), 7.32 (d, J=9.3 Hz, 1H).
70%
Stage #1: at 120℃; for 120 h; Stage #2: With water; sodium hydrogencarbonate In butan-1-ol
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.1H-NMR (CDCl3, stored over molecular sieves): δ=7.06 (d, 1H); 7.79 (d, 1H); 7.92, (d, 1H); 7.96 (d, 1H) ppm.
70%
at 120℃; for 120 h;
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. 1 H-NMR (CDCls, stored over molecular sieves): δ = 7.06 (d, 1 H ); 7.79 (d, 1 H ); 7.92 (d, 1 H); 7.96 (d, 1 H) ppm.
70%
at 120℃; for 120 h;
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. 1H-NMR (CDCls, stored over molecular sieves): δ [ppm]= 7.06 (1 H); 7.79 (1 H); 7.92, (1 H); 7.96 (1 H) ppm.
70%
at 120℃; for 120 h;
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. 1H-NMR (CHLOROFORM-d): δ [ppm] = 7.06 (d, 1 H); 7.79 (d, 1 H); 7.92, (d, 1 H); 7.96 (d, 1 H).
70%
at 120℃; for 120 h;
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. 1H-NMR (CHLOROFORM-d): δ [ppm] = 7.06 (d, 1 H); 7.79 (d, 1 H); 7.92, (d, 1 H); 7.96 (d, 1 H).
70%
at 120℃; for 120 h;
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. 1H-NMR (CHLOROFORM-d): δ [ppm] = 7.06 (1 H); 7.79 (1 H); 7.92 (1 H); 7.96 (1 H).
70%
at 120℃; for 120 h;
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 solid
70%
at 120℃; for 120 h;
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.H-NMR (CHLOROFORM-d): δ [ppm] = 7.06 (d, 1H); 7.79 (d, 1H); 7.92, (d, 1H); 7.96 (d, 1H).
70%
at 120℃; for 120 h;
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. 1H-NMR (CHLOROFORM-d): δ [ppm]=7.06 (1H); 7.79 (1H); 7.92 (1H); 7.96 (1H).
70%
at 120℃; for 120 h;
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.1H-NMR (CHLOROFORM-d): δ [ppm] = 7.06 (d, 1 H); 7.79 (d, 1 H); 7.92, (d, 1 H); 7.96(d, 1 H).
70%
at 120℃; for 120 h;
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.1H-NMR (CDCla, stored over molecular sieves): δ [ppm]= 7.06 (1 H); 7.79 (1 H); 7.92, (1 H); 7.96 (1 H) ppm.
70%
at 120℃; for 120 h;
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) 1H-NMR (CHLOROFORM-d): δ [ppm]=7.06 (d, 1H); 7.79 (d, 1H); 7.92, (d, 1H); 7.96 (d, 1H).
51%
at 100℃; for 5 h;
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).
2 g
at 110℃; for 16 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).
57%
With hydrogen bromide In ethanol at 90℃;
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).
57%
With hydrogen bromide In ethanol at 90℃;
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).
57%
With hydrogen bromide In ethanol at 90℃;
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, CDC13) δ 7.95 (s, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.05 (d, J = 9.3 Hz, 1H).
Stage #1: With hydrogen bromide In water at 120℃; for 0.5 h; Inert atmosphere Stage #2: With sodium hydrogencarbonate In ethanol; water at 0 - 80℃; Inert atmosphere
Synthesis 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, NaHC03 (10 g, 119.69 mmol) and a solution of 6-chloropyridazin-3 -amine (5.0 g, 38.61 mmol) in EtOH (250 mL) was added to the reaction mixture at 0 °C. The resultant reaction mixture was heated up to 80 °C and stirring was continued for another 2h. After consumption of starting material by TLC, the volatiles were removed under reduced pressure. The residue was diluted with NaHC03 solution and extracted with EtOAc. Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by silica gel column chromatography to afford 6-chloroimidazo[l,2-b]pyridazine (3 g, 50percent>) as white solid. 1H-NMR (DMSO-d6, 400 MHz): δ 8.32 (s, 1H), 8.18 (d, 1H), 7.81 (s, 1H), 7.34 (d, 1H); LC-MS: 99.59percent; 154.0 (M+l); (column; X-bridge C-18, (50x3.0 mm, 3.5μ); RT 2.60 min. 5mM NH4OAc in water: ACN; 0.8 ml/min); TLC: 70percent EtOAc/Hexane (Rf: 0.5).
With hydrogenchloride; sodium acetate In ethanol; water at 80 - 85℃; for 16 h;
Sodium 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. 1H-NMR (300 MHz, CDCl3): δ 7.05 (d, J = 9.3 Hz, 1H), 7.78 – 7.93 (m, 3H); MS (ESI) m/z: 153.5 [M+H]+.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 1, p. 24 - 30
8
[ 1453176-84-5 ]
[ 2032-35-1 ]
[ 6775-78-6 ]
Yield
Reaction Conditions
Operation in experiment
57%
With hydrogen bromide In ethanol at 90℃;
[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 O0C and bromoacetaldehyde (2.8g, 0.023 mol) was added. The reaction was refluxed for 20 hrs and n-butanol was removed under reduced pressure. To the reaction mixture, water was added and extracted with EtOAc (5 x 20 ml). The combined organic layers were dried (Na2SO4), concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/hexane) to give 6-Chloro-imidazo[1 ,2- b]pyridazine (4) (690mg, yield = 40percent).
6-Chloroimidazo[1,2-b]pyridazine 41 (6.53 mmol) was dissolved in chloroform (12 mL) and N-chlorosuccinimide (6.53 mmol) added under N2. After stirring for 16 h, the mixture was partitioned between saturated sodium hydrogensulfate solution (25 mL) and chloroform (12 mL). The organic layer was removed, washed with water (2.x.), dried and concentrated to provide 3,6-dichloroimidazo[1,2-b]pyridazine 5 (1.05 g, 85percent) as an orange solid; 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J=9.5 Hz, 1H), 7.74 (s, 1H), 7.12 (d, J=9.5 Hz, 1H). 3,6-Dichloroimidazo[1,2-b]pyridazine 5 (150 mg, 0.8 mmol) and the desired amine (1 mL) were heated in a sealed tube for 16 hr at 120° C. Upon cooling the reaction mixture was concentrated and purified by column chromatography (12 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100percent methylene chloride to 80percent methylene chloride over 30 min at 25 mL/min) to provide the desired product 6.
6-Chloroimidazo[l,2-b]pyridazine (4.95 g, 31.6 mmol) [purchased from Combi-Blocks] was dissolved in 60 mL concentrated sulfuric acid, cooled in an ice bath, and nitric acid (9.9 mL, 158 mmol) was added dropwise while stirring. The reaction was stirred at 0 0C for 30 minutes, then at ambient temperature for 4.5 hours to reach completion. The reaction was poured onto ice, and the resulting aqueous mixture was neutralized with 50percent NaOH aqueous solution and then extracted with EtOAc (3 x 400 mL). The organic layers were combined and washed with water (2 x 400 mL) and brine (400 mL), dried (Na2SO4), filtered and concentrated to yield the product as a yellowish powder (5.7 g, 91percent yield).
86.3%
for 4 h;
In a 500 ml single-necked round bottom flask was added3-Amino-6-chloropyridazine(38.86 g, 300 mmol), 40percent aqueous chloroacetaldehyde (58.88 g, 300 mmol), sodium bicarbonate (30.24 g, 360 mmol) and 260 mLTert-butanol, start magnetic stirrer, the reaction flask was stirred at 80 ° C for 7 hours.TLC detection of raw materials 3-amino-6-chloropyridazine reaction is completed,Nitric acid (22.68 g, 360 mmol) was added and reacted for a further 4 hours with stirring.TLC and GC analysis confirmed that the intermediate 6-chloroimidazo [1,2-b] pyridazine was completely reacted. The reaction mixture was suction filtered and the filter cake was recrystallized from ethyl acetate: n-hexane = 1: 3 to give the pure product 3-nitro-6-chloroimidazo [1,2-b] pyridazine. The filtrate was extracted with ethyl acetate , The extract was removed by rotary evaporation to give the crude product, which was recrystallized from ethyl acetate: n-hexane = 1: 3 to obtain the pure product3-nitro-6-chloroimidazo [1,2-b] pyridazine,After drying, the yield was calculated 86.30percent, purity 99.31percent
78%
at 5 - 75℃; for 4 h;
Intermediate 29 6-Chloro-3-nitro-imidazo[1 ,2-b] pyridazine; To 6-chloro-imidazo[1 ,2-b]pyridazine [WO 2007/013673 A1 Page 42, Preparation 38], (5.0 g, 32.55 mmol) was added concentrated sulfuric acid (7.0 ml_, 131.40 mmol). The resulting solution was cooled to 50C in an ice bath, and yellow fuming nitric acid (5.0 ml_, 119.00 mmol) was added drop-wise at a rate such as to keep the internal temperature below 100C. The ice bath was removed and the reaction continued for 3 hours at room temperature. After this time, the reaction was heated to 75 0C for 1 hour, before pouring the mixture onto crushed ice (60 g). The resulting aqueous slurry was allowed to stand until all the ice had melted, and the precipitate was collected on a Bchner funnel. The crude material was re-crystallized from hot ethanol/water (9:1) to yield 6-chloro-3-nitro-imidazo[1,2-b] pyridazine as a off-white crystalline (5.02 g; 78percent).1H NMR (300 MHz, CDCI3): δ 8.57 (1 H, s), 8.08 (1H, d, J = 9.5 Hz), 7.42 (1H1 d, J = 9.5 Hz). LCMS: 199.04 [M+1], tR = 3.33 min, (MW 198.57).
Reference：
[1] Patent: WO2010/33941, 2010, A1, . Location in patent: Page/Page column 35
[2] Patent: CN106632353, 2017, A, . Location in patent: Paragraph 0013; 0015; 0017; 0018; 0019; 0020
[3] Patent: WO2009/60197, 2009, A1, . Location in patent: Page/Page column 113
[4] Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 1, p. 122 - 131
[5] Patent: US2012/65184, 2012, A1, . Location in patent: Page/Page column 39
15
[ 6775-78-6 ]
[ 6653-96-9 ]
Reference：
[1] Journal of Antibiotics, 2000, vol. 53, # 10, p. 1053 - 1070
[2] Patent: US4942159, 1990, A,
16
[ 6775-78-6 ]
[ 166176-45-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 1, p. 122 - 131
17
[ 6775-78-6 ]
[ 923595-49-7 ]
Yield
Reaction Conditions
Operation in experiment
90%
With N-iodo-succinimide In chloroform at 20℃;
Preparation of 6-chloro-3-iodoimidazo[1,2-b]pyridazine 6-chloroimidazo[1,2-b]pyridazine (2.0 g, 13.0 mmol, 1.0 equiv) in chloroform (20 mL) at room temperature was added N-iodosuccinimide (2.9 g, 13.0 mmol, 1.0 equiv) then stirred vigorously overnight. The reaction mixture was diluted in water and extracted with ethyl acetate. Purification using column chromatography gave 3.3 g of the yellow solid, 90percent: 1H NMR δ 8.21 (d, J=7.6 Hz, 1H), 7.96 (s, 1H), 7.41 (d, J=7.6 Hz, 1H).
75%
With iodine In dimethyl sulfoxide at 20℃; for 36 h;
Example 15 -3 Synthesis of 6-chloro-3-iodo-imidazo[1,2-b]pyridazine 6-chloroimidazo[1,2-b]pyridazine 1*a (28.0 g, 0.182 mol) was dissolved in DMSO (196 ml). Iodine (55.0 g, 0.219 mol) was then added and the reaction mixture was stirred at room temperature for 36 hours. The mixture was poured onto a saturated aqueous sodium bicarbonate solution (250 ml) and extracted with dichloromethane (2 x 250ml). The organic layer was washed with an aqueous solution of sodium meta bisulfite (250 ml) followed by brine (250 ml). It was then dried (Na2SO4) and evaporated under reduced pressure. The residue was recrystallised from ethyl acetate to give 23 g (75 percent) of 6-chloro-3-iodo-imidazo[1,2-b]pyridazine 5* as an off white solid. 1H-NMR (400 MHz, DMSO-d6) : δ = 8.27 (1 H, d, J = 9.5 Hz), 8.02 (1 H, s), 7.46 (1 H, d, J = 9.5 Hz). LCMS-ESI (m/z); found 280.0 [M+H]+.
1.4 g
With N-iodo-succinimide In acetonitrile at 60℃; for 10 h;
Synthesis of 6-chloro-3-iodoimidazo[l , 2-bJpyridazine To a degassed solution of 6-chloroimidazo[l,2-b]pyridazine (1.0 g, 6.51 mmol) and NIS (2.2 g, 9.77 mmol) in MeCN (30 mL) was heated to 60 °C for 10 hours. The reaction mixture was cooled to RT and extract with DCM. The organics were washed with Na2S203 (aq), brine and dried over Na2S04. After concentrated, the crude product was purified by column (PE : EA = 5 : 1) to obtain 6-chloro-3-iodoimidazo[l,2-b]pyridazine (1.4 g, yield: 83percent). 1H- MR (CDC13, 400 MHz) δ 7.83 (s, 1H), 7.80 (d, J= 4.8 Hz, 1H), 7.04 (d, J= 9.6 Hz, 1H). MS(M+H)+: 280.
Reference：
[1] Patent: US2014/256733, 2014, A1, . Location in patent: Page/Page column 0227; 0230-0231
[2] MedChemComm, 2018, vol. 9, # 10, p. 1733 - 1745
[3] Patent: EP2818471, 2014, A1, . Location in patent: Paragraph 0120; 0121
[4] Patent: WO2013/34048, 2013, A1, . Location in patent: Page/Page column 77; 78
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2789 - 2798
[6] Journal of the American Chemical Society, 2015, vol. 137, # 2, p. 592 - 595
18
[ 50-00-0 ]
[ 6775-78-6 ]
[ 675580-49-1 ]
Yield
Reaction Conditions
Operation in experiment
72%
Stage #1: Reflux
Intermediate C6-Chloro-imidazo[1 ,2-b]pyridazine-3-carbaldehyde I Intermediate C(6-Chloro-imidazo[1 ,2-b]pyridazin-3-yl)-methanol (i) To a solution of 6-chloroimidazo[1 ,2-b]pyridazine (1.5 g, 9.8 mmol) in AcOH (50 ml.) was added NaOAc (1.4 g, 17.1 mmol) and paraformaldehyde (1.5 g). The mixture was heated at reflux overnight and then concentrated under reduced pressure. The residue was basified to pH = 12. Then the mixture was filtered and the solid was washed with EtOH to afford (6- chloro-imidazo[1 ,2-b]pyridazin-3-yl)-methanol (1.3 g) in 72percent yield.
72%
With sodium acetate In acetic acidReflux
To a solution of 6-chloroimidazo[1 ,2-b]pyridazine (1 .5 g, 9.8 mmol) in AcOH (50 ml_) was added NaOAc (1 .4 g, 17.1 mmol) and paraformaldehyde (1.5 g). The mixture was heated at reflux overnight and concentrated under reduced pressure. The residue was basified to pH 12. Then the mixture was filtered and the solid was washed with EtOH to afford (6-chloro- imidazo[1 ,2-b]pyridazin-3-yl)-methanol (1.3 g) in 72percent yield.
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine In acetonitrile at 0℃; for 16 h;
Synthesis of methyl imidazo[l,2-b]pyridazine-6-carboxylate: N COOCH3To a stirred solution of 6-chloroimidazo[l,2-b]pyridazine (2.0 g, 13.15 mmol) in ACN:MeOH (60 mL, 1 :1) under N2 bubbling atmosphere were added BINAP (818 mg, 1.31 mmol), Pd(ACN)2Cl2 (341 mg, 1.31 mmol) and Et3N (1.60 g, 15.78 mmol) in a steel bomb. The resultant reaction mixture was agitated under CO atmosphere (150 psi) at 100 °C for 16 h. After full consumption of starting material by TLC, the reaction was diluted with water and extracted with EtOAc. The combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by silica gel column chromatography to afford imidazo[l,2- b]pyridazine-6-carboxylate (1.3 g, 65percent) as brown solid. 1H-NMR (DMSO-d6, 500 MHz): δ 8.51 (s, 1H), 8.27 (d, 1H), 7.94 (s, 1H), 7.72 (d, 1H), 3.97 (s, 3H); LC-MS: 91.14percent; 178 (M++l) (column; X-bridge C-18, (50x3.0 mm, 3.5μ); RT 2.28 min. 5mM NH4OAc: ACN; 0.8 ml/min); TLC: 70percent EtOAc/Hexane (Rf: 0.5).
43%
at 110℃;
A mixture of 6-chloro-imidazo[1,2-b]pyridazine (200 mg, 1 .30 mmol, 1.00 equiv), bis(triphenylphosphine)palladium(Il) dichlonde (200 mg, 0 28 mmol, 0.22 equiv), and tnethylamine (0.5 mL) in methanol (4 mL) was stirred under carbon monoxide ( 10 atm) in a 50-mL pressure reactor overnight at 1 10 °C. The solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 /1 ) to give 1 00 mg (43percent) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3) δ5 8.16 (s, l H), 8.08 (d, J = 9,6 Hz, 1 H), 7.94 (s, 1 H), 7.77 (d, J = 9.6 Hz, 1 H), 4.09 (s, 3H).
43%
at 110℃; Sealed tube
A mixture of 6-chloro-imidazo[ l ,2-b]pyridazine (200 mg, 1 .30 mmol, 1.00 equiv), bis(triphenylphosphine)palladium(Il) dichlonde (200 mg, 0 28 mmol, 0.22 equiv), and tnethylamine (0.5 mL) in methanol (4 mL) was stirred under carbon monoxide ( 10 atm) in a 50-mL pressure reactor overnight at 1 10 °C. The solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 /1 ) to give 1 00 mg (43percent) of the title compound as a yellow solid. NMR (300 MHz, CDCL) 5 8.16 (s, l H), 8.08 (d, J = 9,6 Hz, 1 H), 7.94 (s, 1 H), 7.77 (d, J = 9.6 Hz, 1 H), 4.09 (s, 3H).
43%
at 110℃; Sealed tube
A mixture of 6-chloro-imidazo[1,2-b]pyridazine (200 mg, 1 .30 mmol, 1.00 equiv), bis(triphenylphosphine)palladium(Il) dichlonde (200 mg, 0 28 mmol, 0.22 equiv), and tnethylamine (0.5 mL) in methanol (4 mL) was stirred under carbon monoxide ( 10 atm) in a 50-mL pressure reactor overnight at 1 10 °C. The solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 /1 ) to give 1 00 mg (43percent) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3) δ5 8.16 (s, l H), 8.08 (d, J = 9,6 Hz, 1 H), 7.94 (s, 1 H), 7.77 (d, J = 9.6 Hz, 1 H), 4.09 (s, 3H).
43%
at 110℃;
[0192] Step 2. Imidazo[1,2-blpyridazine-6-carboxylic acid methyl ester. A mixture of 6- chloro-imidazo [1 ,2-b]pyridazine (200 mg, 1.30 mmol, 1.00 equiv), bis(triphenylphosphine)palladium(II) dichloride (200 mg, 0.28 mmol, 0.22 equiv), and triethylamine (0.5 mL) in methanol (4 mL) was stirred under carbon monoxide (10 atm) in a 50-mL pressure reactor overnight at 110 °C. The solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1/1) to give 100 mg (43percent) of the titlecompound as a yellow solid. ‘H NMR (300 MHz, CDC13) ö 8.16 (s, 1H), 8.08 (d, J = 9.6 Hz, 1H), 7.94 (s, 1H), 7.77 (d, J = 9.6 Hz, 1H), 4.09 (s, 3H).
43%
at 110℃;
0200] Step 2. Imidazor 2-b1pyridazine-6-carboxyiic acid methyl ester. A mixture of 6- chloro-imidazo[l,2-b]pyridazine (200 mg, 1.30 mmol, 1.00 equiv), bis(triphenylphosphine)palladium(II) dichloride (200 mg, 0.28 mmol, 0.22 equiv), and triethylamine (0.5 mL) in methanol (4 mL) was stirred under carbon monoxide (10 atm) in a 50-mL pressure reactor overnight at 110 °C. The solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1/1) to give 100 mg (43percent) of the title compound as a yellow solid. 1H NMR (300 MHz, CDC13) δ 8.16 (s, 1H), 8.08 (d, J = 9.6 Hz, 1H), 7.94 (s, 1H), 7.77 (d, J = 9.6 Hz, 1H), 4.09 (s, 3H).
With sulfuric acid; nitric acid; at 0 - 20℃; for 5h;
6-Chloroimidazo[l,2-b]pyridazine (4.95 g, 31.6 mmol) [purchased from Combi-Blocks] was dissolved in 60 mL concentrated sulfuric acid, cooled in an ice bath, and nitric acid (9.9 mL, 158 mmol) was added dropwise while stirring. The reaction was stirred at 0 0C for 30 minutes, then at ambient temperature for 4.5 hours to reach completion. The reaction was poured onto ice, and the resulting aqueous mixture was neutralized with 50% NaOH aqueous solution and then extracted with EtOAc (3 x 400 mL). The organic layers were combined and washed with water (2 x 400 mL) and brine (400 mL), dried (Na2SO4), filtered and concentrated to yield the product as a yellowish powder (5.7 g, 91% yield).
86.3%
With nitric acid; for 4h;
In a 500 ml single-necked round bottom flask was added3-Amino-6-chloropyridazine(38.86 g, 300 mmol), 40% aqueous chloroacetaldehyde (58.88 g, 300 mmol), sodium bicarbonate (30.24 g, 360 mmol) and 260 mLTert-butanol, start magnetic stirrer, the reaction flask was stirred at 80 C for 7 hours.TLC detection of raw materials 3-amino-6-chloropyridazine reaction is completed,Nitric acid (22.68 g, 360 mmol) was added and reacted for a further 4 hours with stirring.TLC and GC analysis confirmed that the intermediate 6-chloroimidazo [1,2-b] pyridazine was completely reacted. The reaction mixture was suction filtered and the filter cake was recrystallized from ethyl acetate: n-hexane = 1: 3 to give the pure product 3-nitro-6-chloroimidazo [1,2-b] pyridazine. The filtrate was extracted with ethyl acetate , The extract was removed by rotary evaporation to give the crude product, which was recrystallized from ethyl acetate: n-hexane = 1: 3 to obtain the pure product3-nitro-6-chloroimidazo [1,2-b] pyridazine,After drying, the yield was calculated 86.30%, purity 99.31%
78%
With sulfuric acid; nitric acid; at 5 - 75℃; for 4h;
Intermediate 29 6-Chloro-3-nitro-imidazo[1 ,2-b] pyridazine; To 6-chloro-imidazo[1 ,2-b]pyridazine [WO 2007/013673 A1 Page 42, Preparation 38], (5.0 g, 32.55 mmol) was added concentrated sulfuric acid (7.0 ml_, 131.40 mmol). The resulting solution was cooled to 50C in an ice bath, and yellow fuming nitric acid (5.0 ml_, 119.00 mmol) was added drop-wise at a rate such as to keep the internal temperature below 100C. The ice bath was removed and the reaction continued for 3 hours at room temperature. After this time, the reaction was heated to 75 0C for 1 hour, before pouring the mixture onto crushed ice (60 g). The resulting aqueous slurry was allowed to stand until all the ice had melted, and the precipitate was collected on a Bchner funnel. The crude material was re-crystallized from hot ethanol/water (9:1) to yield 6-chloro-3-nitro-imidazo[1,2-b] pyridazine as a off-white crystalline (5.02 g; 78%).1H NMR (300 MHz, CDCI3): delta 8.57 (1 H, s), 8.08 (1H, d, J = 9.5 Hz), 7.42 (1H1 d, J = 9.5 Hz). LCMS: 199.04 [M+1], tR = 3.33 min, (MW 198.57).
With sulfuric acid; nitric acid; at 100℃; for 4h;
To a solution of 6-chloroimidazo[1,2-b]pyridazine (I-1) (2.5 g, 16.3 mmol) in conc. H2SO4 (2.5 mL) was added fuming H2NO3 (1.5 mL). The reaction was heated at 100 C. for 4 hours. The mixture was slowly poured onto ice and stirred at room temperature for 0.5 hour. The yellow solid formed was filtered and dried at 40 C. under vacuum overnight to yield 6-chloro-3-nitroimidazo[1,2-b]pyridazine (I-15). MS m/z 199.1 (M+1)+.
Chloroacetaldehyde (9.2 mL, 50% in H2O) wasadded to a solution of 3-amino-6-chloropyridazine (6 g, 46 mmol) in 70 mL n-butanolat room temperature. This mixture was refluxed for 18 h and the then cooled toroom temperature. The resulting precipitate was filtered, washed with butanoland ethyl ether and dissolved in water. NaOH (1N) was added and the extractedwith ethyl acetate and the organic layer was washed with NaHCO3. Theorganic layer was dried over Na2SO4, filtered, andevaporated under reduced pressure to give the compound 1 as a pink amorphous in 92% yield: Mp 116-118 C; Litt1 115-117.5C; 1H NMR (CDCl3):delta 7.35 (d, 1H, J = 9.6 Hz, H-8pyridazine),7.85 (s, 1H, H-2Imid),8.22 (d, 1H, J = 9.6 Hz, H-7pyridazine), 8.34 (s, 1H, H-3Imid). 13CNMR (DMSO-d6): delta117.99 (CH), 119.40 (CH), 128.21 (CH), 134.99 (CH), 137.67 (C), 146.78(C).HPLC: Rt= 1.55 min.
90%
In water; butan-1-ol; at 20℃; for 16h;
Add 3-amino-6-chloropyridazine (3g, 23mmol) and n-butanol (30mL) to a 100mL round bottom flask, add <strong>[107-20-0]chloroacetaldehyde</strong> (4.6mL, 50% aqueous solution) dropwise at room temperature, and reflux for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, n-butanol was distilled off under reduced pressure, then 30 mL of water was added,the pH was adjusted to 7with NaHCO3solution, ethyl acetate (3×50 mL) was extracted, and anhydrous Na2SO4Dry, concentrate the organic phase and separate and purify by column chromatography to obtain 3.1 g of white solid compound 6-chloroimidazo[1,2-b]pyridazine (2), yield 90%,
90%
In water; butan-1-ol; for 16h;Reflux;
Chloroacetaldehyde (4.6 mL, 50% in H2O) was addedto a solution of 3-amino-6-chloropyridazine (3 g, 23 mmol) in 30 mL n-butanolat room temperature. This mixture was refluxed for 16 h and the then cooled toroom temperature. Subsequently, the organic solventwas removed and the resultingresidue was diluted with cold water, the pH was adjusted to 7 with aqueous NaOHand then extracted with EtOAc (3×50 mL). Finally, the resulting organic phases was washedwith brine, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude material was then purified by silica gel columnchromatography to give thecompound 2 in90% yield as an off-white solid. M.p. 115-117 C; 1HNMR (400 MHz, CDCl3): delta 7.35(d, 1H, J = 9.6 Hz), 7.85 (s, 1H), 8.22 (d, 1H, J = 9.6 Hz), 8.34(s, 1H). 13C NMR (100 MHz, CDCl3):delta 146.7, 137.6, 134.9, 128.2, 119.4, 117.9. MS (ESI) m/z: 154.5[M+H]+.
79%
In water; butan-1-ol;Reflux;
To 6-chloropyridazin-3-amine (19.3 g, 0.149 mol) in 1-butanol (150 mL) was added 26.0 mL of <strong>[107-20-0]chloroacetaldehyde</strong> (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 Et2O. 23.6 g of tan solid were recovered and dissolved in water (135 mL). A NaOH solution (1.0 N, 150 mL) was slowly added and copious solids were obtained. AcOEt (150 mL) was added and the aqueous phase was extracted with AcOEt. The organic layer was washed with a saturated solution of NaHCO3 and then dried over MgSO4. After evaporation, 6-chloroimidazo[1,2-b]pyridazine was obtained as a pink solid (18.1 g, 79%).MS (ESI (+)m/z): 153.38 (M+H+)1H NMR (MeOD-d4, 300 MHz), delta 8.14 (s, 1H), 8.05 (d, J=9.3 Hz, 1H), 7.80 (s, 1H), 7.32 (d, J=9.3 Hz, 1H).
70%
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 (55% 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 (70%) of the desired product were isolated in the form of an amorphous white solid.1H-NMR (CDCl3, stored over molecular sieves): delta=7.06 (d, 1H); 7.79 (d, 1H); 7.92, (d, 1H); 7.96 (d, 1H) ppm.
70%
In water; butan-1-ol; at 120℃; for 120h;
5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloracetaldehyde (55% 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 (70%) of the desired product were isolated in the form of an amorphous white solid. 1 H-NMR (CDCls, stored over molecular sieves): delta = 7.06 (d, 1 H ); 7.79 (d, 1 H ); 7.92 (d, 1 H); 7.96 (d, 1 H) ppm.
70%
In butan-1-ol; at 120℃; for 120h;
5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 ml_ (40 mmol) of chloracetaldehyde (55% strength in water) in 15 mL of n-butanol at 120C 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 (70%) of the desired product were isolated in the form of an amorphous white solid. 1H-NMR (CDCls, stored over molecular sieves): delta [ppm]= 7.06 (1 H); 7.79 (1 H); 7.92, (1 H); 7.96 (1 H) ppm.
70%
In butan-1-ol; at 120℃; for 120h;
5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloracetaldehyde (55% 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 (70%) of the desired product were isolated in the form of an amorphous white solid. 1H-NMR (CHLOROFORM-d): delta [ppm] = 7.06 (d, 1 H); 7.79 (d, 1 H); 7.92, (d, 1 H); 7.96 (d, 1 H).
70%
In butan-1-ol; at 120℃; for 120h;
5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of <strong>[107-20-0]chloroacetaldehyde</strong> (55% strength in water) in 15 mL of n-butanol at 120C 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 (70%) of the desired product were isolated in the form of an amorphous white solid. 1H-NMR (CHLOROFORM-d): delta [ppm] = 7.06 (d, 1 H); 7.79 (d, 1 H); 7.92, (d, 1 H); 7.96 (d, 1 H).
70%
In water; butan-1-ol; at 120℃; for 120h;
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 (55% strength in water) in 15 mL of n-butanol at 120C 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 (70%) of the desired product were isolated in the form of an amorphous white solid. 1H-NMR (CHLOROFORM-d): delta [ppm] = 7.06 (1 H); 7.79 (1 H); 7.92 (1 H); 7.96 (1 H).
70%
In water; butan-1-ol; at 120℃; for 120h;
5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of <strong>[107-20-0]chloroacetaldehyde</strong> (55% 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 (70%) of the desired product were isolated in the form of an amorphous white solid
3-(imidazo<1,2-b>pyridazin-6-yl)thiopropanesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol; water
2 Production of 6-(3-sulfamoylpropylthio)imidazo [1,2-b]pyridazine
This product was dissolved in 150 ml of methanol and to the solution was added 150 ml of 2N-potassium hydrogen sulfide-ethanol solution. The mixture was heated at 70° C. for an hour and then distilled under reduced pressure to remove the solvent. Water (200 ml) was added to the residue. The mixture was adjusted to pH 3 with hydrochloric acid and then extracted with 200 ml of chloroform. The chloroform layer was dried over magnesium sulfate and distilled to remove the solvent, thereby yielding 10.8 g of crude 3-mercaptopropanesulfomamide. This product was dissolved in methanol (200 ml), to which 11.8 g of 28 W/W % sodium methoxide-methanol solution and 8.0 g of 6-chloroimidazo[1,2-b]pyridazine were added. The mixture was refluxed for 3 hours, concentrated to dryness under reduced pressure. To the residue was added 100 ml of water and the aqueous solution was extracted with 100ml of ethyl acetate-tetrahydrofuran (1:1) solution. The organic layer was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was subjected to a silica gel column chromatography, developing with 4 V/V % methanol-chloroform. The corresponding fractions were concentrated. The residue was recrystallized from methanol to obtain 5.6 g of the title compound.
REFERENCE EXAMPLE 5 Production of 3.6-dichloroimidazo[1,2-b]pyridazine 6-Chloroimidazo[1,2-b]pyridazine (7.68 g) was added to 150 ml of carbon tetrachloride, to which 7.0 g of N-chlorossuccinimide were added and refluxed for 2 hours. After cooling, the precipitated crystals were filtered off. The filtrate was washed in turn with 1N-sodium hydroxide aqueous solution, 1N-hydrochloric acid and water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was washed with diethyl ether to obtain 7.13 g of 3.6-dichloroimidazo[1,2-b]pyridazine. mp: 120-121 C. NMR(CDCl3)delta: 7.12(1H,d), 7.75(1H,s), 7.92(1H,d).
With N-chloro-succinimide; In chloroform; for 16.0h;
6-Chloroimidazo[1,2-b]pyridazine 41 (6.53 mmol) was dissolved in chloroform (12 mL) and N-chlorosuccinimide (6.53 mmol) added under N2. After stirring for 16 h, the mixture was partitioned between saturated sodium hydrogensulfate solution (25 mL) and chloroform (12 mL). The organic layer was removed, washed with water (2×), dried and concentrated to provide 3,6-dichloroimidazo[1,2-b]pyridazine 5 (1.05 g, 85%) as an orange solid; 1H NMR (500 MHz, CDCl3) delta 7.92 (d, J=9.5 Hz, 1H), 7.74 (s, 1H), 7.12 (d, J=9.5 Hz, 1H). 3,6-Dichloroimidazo[1,2-b]pyridazine 5 (150 mg, 0.8 mmol) and the desired amine (1 mL) were heated in a sealed tube for 16 hr at 120 C. Upon cooling the reaction mixture was concentrated and purified by column chromatography (12 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 30 min at 25 mL/min) to provide the desired product 6.
5-(imidazo[1,2-b]pyridazin-6-yl)-3-trifluoromethylpyridin-2-ylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 120℃; for 0.25h;
Stage A.2: 5-lmidazo[1,2-b]pyridazin-6-yl-3-trifluoromethyl-pyridin-2-ylamine (II). 6-Chloro-imidazo[1,2-b]pyridazine (I) (384 mg; 2.5 mMol) is dissolved in DMF (15 mL), followed by addition of 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (example 4; stage 4.2) (864 mg; 3 mmol), PdCI2(PPh3) (30 mg) and potassium carbonate (1 M soln. in H2O; 6.25 mL). The mixture is heated under stirring to 120C for 15 min. After cooling to RT EtOAc (150 mL) is added and the organic layer is washed with water (2 x). After removal of the solvent under reduced pressure, the crude product is purified by flash chromatography (30 g Silica gel [0.040-0.063mm] Merck 1.09.385.1000]; eluting with CH2CI2 /MeOH 98:2), to obtain the title compound (618 mg) as as yellowish powder (618 mg); MS(ESI+): m/z= 280.1 (M+H)+; HPLC: tRet = 3.717 minutes (System 2).
With potassium carbonate In 1-methyl-pyrrolidin-2-one at 120℃; for 18h;
11 Methyl 3-(imidazo[1,2-b]pyridazin-6-yloxy)benzoate (7a)
A mixture of 3 (1.54 g, 10 mmol), methyl 3-hydroxybenzoate (1.98 g, 13 mmol), and K2CO3 (4.15 g, 30 mmol) in NMP (10 mL) was stirred at 120 °C for 18 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water and concentrated in vacuo. The residue was purified by basic silica gel column chromatography (hexane/EtOAc 90:10 to 20:80), silica gel column chromatography (hexane/EtOAc 60:40 to 0:100), and trituration with diisopropyl ether to give 7a (1.72 g, 64%) as a white solid. 1H NMR (DMSO-d6) δ 3.87 (3H, s), 7.16 (1H, d, J = 9.5 Hz), 7.60-7.68 (3H, m), 7.79-7.83 (1H, m), 7.84-7.93 (1H, m), 8.05 (1H, s), 8.19 (1H, d, J = 9.5 Hz).
With 1-methyl-pyrrolidin-2-one; potassium carbonate
446 Production of methyl 3-(imidazo[1,2-b]pyridazin-6-yloxy)benzoate
Example 446 Production of methyl 3-(imidazo[1,2-b]pyridazin-6-yloxy)benzoate A mixture of 6-chloroimidazo[1,2-b]pyridazine (1536 mg, 10.0 mmol), methyl 3-hydroxybenzoate (1978 mg, 13.0 mmol), potassium carbonate (4146 mg, 30.0 mmol) and N-methylpyrrolidone (10 mL) was stirred at 120° C. for 18 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane/ethyl acetate=90/10→20/80). The objective fraction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→0/100) and precipitated from diisopropyl ether to give the title compound (1722 mg, 6.4 mmol, yield 64%) as a white solid. 1H-NMR (DMSO-d6, 300 MHz) δ 3.87 (3H, s), 7.16 (1H, d, J=9.5 Hz), 7.60-7.68 (3H, m), 7.79-7.83 (1H, m), 7.84-7.93 (1H, m), 8.05 (1H, s), 8.19 (1H, d, J=9.5 Hz).
Intermediate C6-Chloro-imidazo[1 ,2-b]pyridazine-3-carbaldehyde I Intermediate C(6-Chloro-imidazo[1 ,2-b]pyridazin-3-yl)-methanol (i) To a solution of 6-chloroimidazo[1 ,2-b]pyridazine (1.5 g, 9.8 mmol) in AcOH (50 ml.) was added NaOAc (1.4 g, 17.1 mmol) and paraformaldehyde (1.5 g). The mixture was heated at reflux overnight and then concentrated under reduced pressure. The residue was basified to pH = 12. Then the mixture was filtered and the solid was washed with EtOH to afford (6- chloro-imidazo[1 ,2-b]pyridazin-3-yl)-methanol (1.3 g) in 72% yield.
72%
With sodium acetate; In acetic acid;Reflux;
To a solution of 6-chloroimidazo[1 ,2-b]pyridazine (1 .5 g, 9.8 mmol) in AcOH (50 ml_) was added NaOAc (1 .4 g, 17.1 mmol) and paraformaldehyde (1.5 g). The mixture was heated at reflux overnight and concentrated under reduced pressure. The residue was basified to pH 12. Then the mixture was filtered and the solid was washed with EtOH to afford (6-chloro- imidazo[1 ,2-b]pyridazin-3-yl)-methanol (1.3 g) in 72% yield.
With 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine;dichloro bis(acetonitrile) palladium(II); In acetonitrile; for 16.0h;
Synthesis of methyl imidazo[l,2-b]pyridazine-6-carboxylate: N COOCH3To a stirred solution of 6-chloroimidazo[l,2-b]pyridazine (2.0 g, 13.15 mmol) in ACN:MeOH (60 mL, 1 :1) under N2 bubbling atmosphere were added BINAP (818 mg, 1.31 mmol), Pd(ACN)2Cl2 (341 mg, 1.31 mmol) and Et3N (1.60 g, 15.78 mmol) in a steel bomb. The resultant reaction mixture was agitated under CO atmosphere (150 psi) at 100 C for 16 h. After full consumption of starting material by TLC, the reaction was diluted with water and extracted with EtOAc. The combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by silica gel column chromatography to afford imidazo[l,2- b]pyridazine-6-carboxylate (1.3 g, 65%) as brown solid. 1H-NMR (DMSO-d6, 500 MHz): delta 8.51 (s, 1H), 8.27 (d, 1H), 7.94 (s, 1H), 7.72 (d, 1H), 3.97 (s, 3H); LC-MS: 91.14%; 178 (M++l) (column; X-bridge C-18, (50x3.0 mm, 3.5mu); RT 2.28 min. 5mM NH4OAc: ACN; 0.8 ml/min); TLC: 70% EtOAc/Hexane (Rf: 0.5).
43%
With bis-triphenylphosphine-palladium(II) chloride; triethylamine; at 110.0℃; under 7600.51 Torr;
A mixture of 6-chloro-imidazo[1,2-b]pyridazine (200 mg, 1 .30 mmol, 1.00 equiv), bis(triphenylphosphine)palladium(Il) dichlonde (200 mg, 0 28 mmol, 0.22 equiv), and tnethylamine (0.5 mL) in methanol (4 mL) was stirred under carbon monoxide ( 10 atm) in a 50-mL pressure reactor overnight at 1 10 C. The solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 /1 ) to give 1 00 mg (43%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3) delta5 8.16 (s, l H), 8.08 (d, J = 9,6 Hz, 1 H), 7.94 (s, 1 H), 7.77 (d, J = 9.6 Hz, 1 H), 4.09 (s, 3H).
43%
With bis-triphenylphosphine-palladium(II) chloride; triethylamine; at 110.0℃;Sealed tube;
A mixture of 6-chloro-imidazo[ l ,2-b]pyridazine (200 mg, 1 .30 mmol, 1.00 equiv), bis(triphenylphosphine)palladium(Il) dichlonde (200 mg, 0 28 mmol, 0.22 equiv), and tnethylamine (0.5 mL) in methanol (4 mL) was stirred under carbon monoxide ( 10 atm) in a 50-mL pressure reactor overnight at 1 10 C. The solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 /1 ) to give 1 00 mg (43%) of the title compound as a yellow solid. NMR (300 MHz, CDCL) 5 8.16 (s, l H), 8.08 (d, J = 9,6 Hz, 1 H), 7.94 (s, 1 H), 7.77 (d, J = 9.6 Hz, 1 H), 4.09 (s, 3H).
43%
With bis-triphenylphosphine-palladium(II) chloride; triethylamine; at 110.0℃;Sealed tube;
A mixture of 6-chloro-imidazo[1,2-b]pyridazine (200 mg, 1 .30 mmol, 1.00 equiv), bis(triphenylphosphine)palladium(Il) dichlonde (200 mg, 0 28 mmol, 0.22 equiv), and tnethylamine (0.5 mL) in methanol (4 mL) was stirred under carbon monoxide ( 10 atm) in a 50-mL pressure reactor overnight at 1 10 C. The solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1 /1 ) to give 1 00 mg (43%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDCl3) delta5 8.16 (s, l H), 8.08 (d, J = 9,6 Hz, 1 H), 7.94 (s, 1 H), 7.77 (d, J = 9.6 Hz, 1 H), 4.09 (s, 3H).
43%
With bis-triphenylphosphine-palladium(II) chloride; triethylamine; at 110.0℃; under 7600.51 Torr;
[0192] Step 2. Imidazo[1,2-blpyridazine-6-carboxylic acid methyl ester. A mixture of 6- chloro-imidazo [1 ,2-b]pyridazine (200 mg, 1.30 mmol, 1.00 equiv), bis(triphenylphosphine)palladium(II) dichloride (200 mg, 0.28 mmol, 0.22 equiv), and triethylamine (0.5 mL) in methanol (4 mL) was stirred under carbon monoxide (10 atm) in a 50-mL pressure reactor overnight at 110 C. The solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1/1) to give 100 mg (43%) of the titlecompound as a yellow solid. ?H NMR (300 MHz, CDC13) oe 8.16 (s, 1H), 8.08 (d, J = 9.6 Hz, 1H), 7.94 (s, 1H), 7.77 (d, J = 9.6 Hz, 1H), 4.09 (s, 3H).
43%
With bis-triphenylphosphine-palladium(II) chloride; triethylamine; at 110.0℃; under 7600.51 Torr;
0200] Step 2. Imidazor 2-b1pyridazine-6-carboxyiic acid methyl ester. A mixture of 6- chloro-imidazo[l,2-b]pyridazine (200 mg, 1.30 mmol, 1.00 equiv), bis(triphenylphosphine)palladium(II) dichloride (200 mg, 0.28 mmol, 0.22 equiv), and triethylamine (0.5 mL) in methanol (4 mL) was stirred under carbon monoxide (10 atm) in a 50-mL pressure reactor overnight at 110 C. The solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1/1) to give 100 mg (43%) of the title compound as a yellow solid. 1H NMR (300 MHz, CDC13) delta 8.16 (s, 1H), 8.08 (d, J = 9.6 Hz, 1H), 7.94 (s, 1H), 7.77 (d, J = 9.6 Hz, 1H), 4.09 (s, 3H).
With dichloro bis(acetonitrile) palladium(II); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; triethylamine; In acetonitrile; at 100.0℃; under 7757.43 Torr; for 16.0h;Inert atmosphere;
[0517] Synthesis of methyl imidazo[l,2-b]pyridazine-6-carboxylate: [0518] To a stirred solution of 6-chloroimidazo[l,2-b]pyridazine (2.0 g, 13.15 mmol) in ACN:MeOH (60 mL, 1 : 1) under N2 bubbling atmosphere were added BINAP (818 mg, 1.31 mmol), Pd(ACN)2Cl2 (341 mg, 1.31 mmol) and Et3N (1.60 g, 15.78 mmol) in a steel bomb. The resultant reaction mixture was agitated under CO atmosphere (150 psi) at 100 C for 16 h. After full consumption of starting material by TLC, the reaction was diluted with water and extracted with EtOAc. The combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by silica gel column chromatography to afford imidazo[l,2-b]pyridazine-6-carboxylate (1.3 g, 65%) as brown solid. 1H-NMR (DMSO-d6, 500 MHz): delta 8.51 (s, 1H), 8.27 (d, 1H), 7.94 (s, 1H), 7.72 (d, 1H), 3.97 (s, 3H); LC-MS: 91.14%; 178 (M++l) (column; X- bridge C-18, (50x3.0 mm, 3.5mu); RT 2.28 min. 5mM NH4OAc: ACN; 0.8 ml/min); TLC: 70% EtOAc/Hexane (Rf: 0.5).
Preparation of 6-chloroimidazo[1,2-b]pyridazine Bromoacetaldehyde diethylacetal (13.7 g, 69.5 mmol, 1.8 equiv) was added to hydrobromic acid (4.0 mL) and heated to reflux for 1.5 h. The reaction mixture was cooled to rt then poured into a reaction flask containing excess sodium bicarbonate in isopropanol. The solution was stirred for 3 min and then filtered. To the mother liquor was added 3-amino-6-chloropyridazine (5.0 g, 38.6 mmol, 1.0 equiv) and heated to reflux for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate. Purification using column chromatography gave 5.1 g of the brown solid, 86%: 1H NMR (400 MHz, CDCl3) delta 7.89 (s, 1H), 7.88 (d, J=9.3 Hz, 1H), 7.74 (s, 1H), 7.01 (d, J=9.3 Hz, 1H).
85%
PREPARATION 1; 3-Bromo-6-chloroimidazo[1,2-b]pyridazine a) 6-Chloroimidazo[1,2-o]pyridazineHydrobromic acid (48% 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, 85%) as a beige solid.LRMS (m/z): 154 (M+1)+.1H-NMR delta (300 MHz, CDCI3): 7.08 (d, 1 H), 7.81 (s, 1 H), 7.88 - 7.99 (m, 2H).
85%
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 48% 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 ºC. 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 ºC of 6-chloropyridazin-3-amine (5.0 g, 38.60 mmol) in n-butanol (8 mL). The resulting mixture was heated at 130 ºC 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, 85%) as a beige solid. LRMS (m/z): 154 (M+1)+. 1H-NMR delta (300 MHz, CDCl3): 7.08 (d, 1H), 7.81 (s, 1H), 7.88 -7.99 (m, 2H).
59%
Example 15 -1 Synthesis of 6-chloro-imidazo[1,2-b]pyridazine A Solution of 48% HBr (25.2ml) was added to bromoacetaldehyde diethyl acetal (104 g, 0.618 mol) and the resultant mixture was heated to reflux for 1.5 hrs. The reaction mixture was then poured into a suspension of NaHCO3 (20.0 g) in isopropyl alcohol (800 ml). The solution was filtered and 3-amino-6-chloropyridazine (40.0 g, 0.309 mol) was added to the filtrate and the mixture heated at reflux for 2 hours. The mixture was cooled, evaporated to dryness, dissolved in ethyl acetate (1 L), washed with a saturated aqueous solution of NaHCO3 (500 ml), followed by brine (500 ml). The organic layer was then dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient elution with hexane and ethyl acetate 0 to 100%) to give 28.0 g (59%) of 6-chloro-imidazo[1,2-b]pyridazine 1*a as a brown solid. 1H-NMR (400 MHz, DMSO-d6): 8.35 (1H, d, J = 0.9 Hz), 8.23 (1 H, d, J = 9.5 Hz), 7.86 (1 H, d, J = 1.1 Hz), 7.36 (1 H, d, J = 9.5 Hz). LCMS-ESI (m/z); found 154.0 [M+H]+.
Preparation of 6-chloro-3-iodoimidazo[1,2-b]pyridazine 6-chloroimidazo[1,2-b]pyridazine (2.0 g, 13.0 mmol, 1.0 equiv) in chloroform (20 mL) at room temperature was added N-iodosuccinimide (2.9 g, 13.0 mmol, 1.0 equiv) then stirred vigorously overnight. The reaction mixture was diluted in water and extracted with ethyl acetate. Purification using column chromatography gave 3.3 g of the yellow solid, 90%: 1H NMR delta 8.21 (d, J=7.6 Hz, 1H), 7.96 (s, 1H), 7.41 (d, J=7.6 Hz, 1H).
90%
With N-iodo-succinimide; In methanol;Reflux;
At room temperature, 294 NIS (1.50 g, 6.50 mmol) was added into the solution of 295 6-chloro-3-imidazo[1,2-b]pyridazine (1.0 g, 6.50 mmol) in 43 methanol (10 mL) in portions, and the reaction was stirred under reflux overnight. The reaction was quenched by adding saturated solution of 178 sodium thiosulfate, extracted with dichloromethane (50 mL×3), the organic layer was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 1.13 g of a yellow solid. Yield was 90.0%. LC-MS(APCI): m/z=290.1 (M+1)
75%
With iodine; In dimethyl sulfoxide; at 20℃; for 36h;
Example 15 -3 Synthesis of 6-chloro-3-iodo-imidazo[1,2-b]pyridazine 6-chloroimidazo[1,2-b]pyridazine 1*a (28.0 g, 0.182 mol) was dissolved in DMSO (196 ml). Iodine (55.0 g, 0.219 mol) was then added and the reaction mixture was stirred at room temperature for 36 hours. The mixture was poured onto a saturated aqueous sodium bicarbonate solution (250 ml) and extracted with dichloromethane (2 x 250ml). The organic layer was washed with an aqueous solution of sodium meta bisulfite (250 ml) followed by brine (250 ml). It was then dried (Na2SO4) and evaporated under reduced pressure. The residue was recrystallised from ethyl acetate to give 23 g (75 %) of 6-chloro-3-iodo-imidazo[1,2-b]pyridazine 5* as an off white solid. 1H-NMR (400 MHz, DMSO-d6) : delta = 8.27 (1 H, d, J = 9.5 Hz), 8.02 (1 H, s), 7.46 (1 H, d, J = 9.5 Hz). LCMS-ESI (m/z); found 280.0 [M+H]+.
24%
With N-iodo-succinimide; In acetonitrile; at 20℃; for 14h;Inert atmosphere;
Compound 23 (4.60g, 30.06mmol) was dissolved in acetonitrile (30mL) was added NIS (7.44g, 33.07 mmol), nitrogen was purged of air and stirred at room temperature for 14 hours under protection. The reaction solution was concentrated, purified by silica gel column chromatography, the mobile phase system methylene chloride and methanol (DCM: MeOH = 50: 1). 5.12 g of a white solid 24 was obtained in a two step yield of 24%.
1.4 g
With N-iodo-succinimide; In acetonitrile; at 60℃; for 10h;
Synthesis of 6-chloro-3-iodoimidazo[l , 2-bJpyridazine To a degassed solution of 6-chloroimidazo[l,2-b]pyridazine (1.0 g, 6.51 mmol) and NIS (2.2 g, 9.77 mmol) in MeCN (30 mL) was heated to 60 C for 10 hours. The reaction mixture was cooled to RT and extract with DCM. The organics were washed with Na2S203 (aq), brine and dried over Na2S04. After concentrated, the crude product was purified by column (PE : EA = 5 : 1) to obtain 6-chloro-3-iodoimidazo[l,2-b]pyridazine (1.4 g, yield: 83%). 1H- MR (CDC13, 400 MHz) delta 7.83 (s, 1H), 7.80 (d, J= 4.8 Hz, 1H), 7.04 (d, J= 9.6 Hz, 1H). MS(M+H)+: 280.
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 20℃; for 6h; Inert atmosphere; Reflux;
1
Step 1: 4-boronobenzoic acid (11.88 g, 71.61 mmol), K3P04 (27.60 g, 13.02 mmol) and Pd(PPh3)4 (3.75 g, 3.25 mmol) were added sequentially to a solution of 6-chloroimidazo[l,2- b]pyridazine (10 g, 65.10 mmol) in a mixture of l,4-dioxane/H20 (250:50 mL) at room temperature under argon atmosphere. The reaction mixture was refluxed for 6 h and was diluted with water (100 mL) and extracted with EtOAc (3x100 mL). The combined aqueous layer was acidified to pH 2 using citric acid. The precipitate was isolated by filtration and dried under reduced pressure to afford 4-(imidazo[ 1 ,2-b]pyridazin-6-yl)benzoic acid (4.5 g, 57%) as an off-white solid.1H NMR (400 MHz, DMSO-a?6) δ 13.01 (bs, 1H), 8.04 (s, 1H), 8.3-8.01 (m, 5H), 7.85 (d, J= 7.2 Hz, 2H); MS (ESI) m/z 240 [M+ H]+.
57%
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water for 6h; Inert atmosphere; Reflux;
13.1 Intermediate 13: 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)benzoic acid
4-boronobenzoic acid (11.88 g, 71.61 mmol), K3PO4 (27.60 g, 13.02 mmol) and Pd(PPh3)4 (3.75 g, 3.25 mmol) were added sequentially to a solution of 6-chloroimidazo[1,2-b]pyridazine (10 g, 65.10 mmol) in a mixture of 1,4-dioxane/H2O (250:50 mL) at room temperature under argon atmosphere. The reaction mixture was refluxed for 6 h and was diluted with water (100 mL) and extracted with EtOAc (3*100 mL). The combined aqueous layer was acidified to pH 2 using citric acid. The precipitate was isolated by filtration and dried under reduced pressure to afford 4-(imidazo[1,2-b]pyridazin-6-yl)benzoic acid (4.5 g, 57%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.01 (bs, 1H), 8.04 (s, 1H), 8.3-8.01 (m, 5H), 7.85 (d, J=7.2 Hz, 2H); MS (ESI) m/z 240 [M+H]+.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 100℃; for 15h; Inert atmosphere;
8.1 Preparation of 4-(imidazo[l ,2-b]pyridazin-6-yl)benzoic acid
To a solution of 6-chloroimidazo [1, 2-b] pyridazine (2 g, 13.07 mmol) in 1, 4-dioxane (20 mL) and water (10 rnL) were successively added 4-boronobenzoic acid (2.58 g, 15.87 mmol),K2C03 (3.6 g, 0.81 mmol), and Pd(PPh3)4 (0.75 g, 6.5 mmol). The reaction mixture was heated at 100 °C for 15 h under argon. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phase was washed with brine (1 x 50 mL), dried over Na2S04, filtered and concentrated under vacuum to afford 4-(imidazo[l,2-b]pyridazin-6-yl)benzoic acid (2 g, 64%) as a white solid (LC-MS 84%). 1H NMR (400 MHz, DMSO-i) δ 13.01 (bs, 1H), 8.04 (s, 1H), 8.3-8.01 (m, 5H), 7.85 (d, J= 7.2 Hz, 2H); MS (ESI) m/z 240 [M+ H]+.
6-chloro-8-(oxetan-3-yl)imidazo[1,2-b]pyridazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
With sulfuric acid; dihydrogen peroxide; iron(II) sulfate; In dimethyl sulfoxide; at 20℃;
Step 1 : To a solution of 6-chloroimidazo[l,2-b]pyridazine (1.0 equiv.) in DMSO (0.1 M) was added <strong>[26272-85-5]3-iodooxetane</strong> (4.0 equiv.), sulfuric acid (2.0 equiv.) and FeS04 (0.6 equiv.) at rt. To this solution was added hydrogen peroxide (6.0 equiv.) dropwise. After 2 min, another 0.6 equiv. of FeS04 was added and the reaction was stirred for 30 min. Then, another 6.0 equiv. of hydrogen peroxide and 0.6 equiv. of FeS04 were added and the reaction was stirred overnight at rt. The mixture was quenched by the addition of sat. sodium bicarbonate and extracted twice with ethyl acetate. The organic phase was dried with magnesium sulfate, filtered and concentrated. The residue was purified via reverse phase prep-HPLC and the pure fractions were neutralized with a PL-HCO3 resin. Upon concentration under vacuo, 6-chloro-8-(oxetan-3-yl)imidazo| T,2-b jpyridazine was isolated in 27% yield. LCMS (m/z) (Mu+) - 210.0, Rt - 0.41 mm.
With palladium diacetate; potassium carbonate; triphenylphosphine; In toluene; at 110℃; for 30.0h;Inert atmosphere;
General procedure: In two neck 50 mL round bottom flask dry under nitrogen ethylN-imidazo[1,2-b]pyridazin-6-ylcarbamate (0.104 g, 0.66 mmol) was placed inanhydrous toluene (2.1 mL). After 10 min, 3-bromopyridin (0.083 mL, 0.66 mmol),Pd(OAc)2 (0.045 g, 10%), triphenylphosphine(0.035 g,20%), was added and then K2CO3 (0.184 g, 1.29mmol). The mixture was heated at 110C during 8 h. After cooling to roomtemperature, the solvent was evaporated. The crude residue was diluted in AcOEtand washed with NaCl solution. The organic layer was dried over Na2SO4,filtered, and evaporated under reduced pressure. The crude residue was purifiedby chromatography on silica gel using Cyclohexane-AcOEt (7:3). Evaporation ofthe eluent in vacuum gave the desired compound in 6.8% yield (0.013 g) as awhite powder.
With palladium on activated charcoal; hydrogen; triethylamine; In tetrahydrofuran; methanol; for 16.0h;
To a stirred solution of 6-chloroimidazo[1,2-bjpyridazine (800 mg, 5.21 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL) was added triethylamine (0.8 mL, 5.74mmol) followed by Pd/C (100 mg, 0.094 mmol). The mixture was stirred under hydrogen atmosphere for 16h. The reaction mixture was filtered through celite and the celite bed was washed with methanol. The combined filtrate was concentrated then suspended in water and extracted with ethyl acetate (3x). The organic layer was dried over Na2SO4 and filtered to give the imidazo[1,2-bjpyridazine (550 mg, 87%) as off white solid. LCMS[m/z 120 (M+H)j; ?H NMR (300 MHz, DMSO-d6) oe 8.51 (dd, J4.53, 1.51 Hz, 1H) 8.29(d,J0.76Hz, 1 H) 8.05-8.19(m, 1 H)7.79(d,J1.13 Hz, 1 H) 7.22 (dd,J=9.44,4.53 Hz, 1 H).
10.1 Step 1: 6-Methoxyimidazo[1,2-b]pyridazine 46
Sodium methoxide (7.35 eq., 7.76g, 143.6 mmol) was added to a solution of 6-chloroimidazo[1 ,2-bb]pyridazine ( 3.0 g, 19.54 mmol) in anhydrous methanol (8 ml) at ambient temperature and the reaction mixture stirred for 18 hours. The volatiles were removed by evaporation and the yellow oily residue was dissolved in dichloromethane (100 ml). The solution was washed with water (5x100 ml) until aqueous wash became neutral. The organic solution was dried (MgSC ) and the solvent removed. The title compound (m = 8.87 g, yield = 91%) was obtained as a white solid. 1H NMR (400 MHz, DMSO -cfe) d 7.36 (d, J = 9.3 Hz , 1 H), 6.85 (d, J = 9.3 Hz, 1 H), 6.61 (s, 1 H)13C NMR (101 MHz, CDCIs) d 160.2, 137.3, 132.4, 127.3, 116.8, 112.1 , 54.4
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