6-Chloro-5-methylpyridazin-3-amine

[Linholter, S., et a/, Acta Chem. Scand. 15: 1660-1666 (1961 )]. To a solution of 3, 6-dichloro-4-methyl-pyridazine (200 mg) in ethanol (3ml) was added liquid ammonia (3 ml). The reaction mixture was heated at 120 A mixture of 3, 6-dichloro-4-methylpyridazine (5 g, 30.7 mmol) and concentrated NH40H solution (100 ml) was heated to 120° in a sealed autoclave for 18 hrs at 6 bar. The mixture was cooled to r.t, diluted with water (200 ml) and stirred in an ice bath for 2 hrs. The solid was collected by filtration, washed with water and dried. The filtrate was extracted with CHIn a sealed flask, 3, 6-dichloro-4-methylpyridazine (27 g, 161 mmol) was suspended in aqueous ammonia (25percent, 300 mL). The reaction mixture was heated at 110 °C for 48 hours (turned into solution after 1 hour). After cooling to room temperature, the reaction was poured into CH2C12, and the organic phase was separated, dried over Na2SO4, and concentrated under vacuum, to give 22.4 g of 6-chloro-4-methyl-pyridazin-3-amine and 6-chloro-5-methyl-pyridazin-3-amine as a mixture of regioisomers which were used directly in the next step.In a sealed flask, 3, 6-dichloro-4-methylpyridazine (27 g, 161 mmol) was suspended in aqueous ammonia (25percent, 300 mL). The reaction mixture was heated at 110 °C for 48 hours (turned into solution after 1 hour). After cooling to room temperature, the reaction was poured into CH2C12, and the organic phase was separated, dried over Na2SO4, and concentrated under vacuum, to give 22.4 g of 6-chloro-4-methyl-pyridazin-3-amine and 6-chloro-5-methyl-pyridazin-3-amine as a mixture of regioisomers which were used directly in the next step.SYNTHESIS OF IMIDAZO[1 , 2-B]PYRIDAZINE COMPOUNDS AND 7- METHYL-IMIDAZO[1 , 2-B]PYRIDAZINE COMPOUNDS [0177] Additional compounds of the invention, including illustrative compounds set forth in Table VII, were made according to the following synthetic examples. In these examples, Compound 7-12 was prepared as described above in Example 2, while compound 11 was prepared as follows:β-chloroS-methylpyridazin-S-amine 7:for 48 h.[0178] 3, 6-dichloro-4-methylpyridazine 6 (1 g) was dissolved in 5 mL of ethanol and was added ammonium hydroxide (10 mL). The resulting reaction mixture was sealed in a pressure bottle and heated to 100 [Linholter, S., et a/, Acta Chem. Scand. 15: 1660-1666 (1961 )]. To a solution of 3, 6-dichloro-4-methyl-pyridazine (200 mg) in ethanol (3ml) was added liquid ammonia (3 ml). The reaction mixture was heated at 120 0C in a sealed tube for 12 h. After cooling to room temperature, methanol and ammonia were evaporated. The residue was purified by flash chromatography (ethyl acetate) to afford 153 mg of mixture of 7 and 10 (1 :1 ), (87%), which was used without any further separation.A mixture of 3, 6-dichloro-4-methylpyridazine (5 g, 30.7 mmol) and concentrated NH40H solution (100 ml) was heated to 120 in a sealed autoclave for 18 hrs at 6 bar. The mixture was cooled to r.t, diluted with water (200 ml) and stirred in an ice bath for 2 hrs. The solid was collected by filtration, washed with water and dried. The filtrate was extracted with CH2Cl2/MeOH (9: 1). The organic was washed with brine, dried over MgSC^, filtered and evaporated. The precipitate from the reaction mixture and the solid isolated by extraction were combined. This crude product was purified by column chromatography using a CH2Cl2/MeOH gradient as eluent, to provide 6-chloro-4-methylpyridazin-3-amine (456 mg, 10%) and 6-chloro-5-methylpyridazin- 3-amine (350 mg, 8%>), both as off-white solids. MS: M = 144.1 (M+H)+ (both isomers)Example 136 Alternative Method 16 2-Chloro-N-{5-methyl-6-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridazin-3-yl}-4-trifluoromethyl-benzenesulfonamide (136) Step 1: 6-Chloro-5-methyl-pyridazin-3-ylamine and 6-chloro-4-methyl-pyridazin-3-ylamine; 3, 6-Dichloro-4-methylpyridazine (10 g) was mixed with ammonium hydroxide (62 mls) and heated at 135 C. in a sealed vessel at 12 Bar for 20 hours. The mixture was allowed to cool and all volatiles removed in vacuo. The crude material was pre-absorbed onto silica using methanol and purified by flash chromatography using methanol 0-5% in dichloromethane. Two fractions were isolated, Fraction 1 3.86g of a 1:0.66 Isomer A to Isomer B and Fraction 2-3.40g of a 1:2.5 mixture Isomer A to Isomer B. Fraction 1 1H NMR (CDCl3) 7.0 (1H, s) 6.6 (0.66H, s) 4.9 (broad) 2.25 (3H, s) 2.15 (2H, s). Fraction 2 1H NMR (CDCl3) 7.0 (1H, s) 6.6 (2.5H, s) 4.7(broad) 2.25 (8H, s) 2.1(3H, s)In a 20 ml microwave flask 3, 6-dichloro-4-methylpyridazine (2.30 g, 14.11 mmol) and a 7 M solution OfNH3 in methanol (10.08 ml, 70.6 mmol) were added and heated at 140 C for 4 h under microwave irradiation. After this time the dark brown solution was evaporated and columned on silica gel (flash master, DCM/MeOH form 100/0 to 80/20). Collected fractions gave (0.91 g, 6.33 mmol, 45%) of a 2/1 mixture of 6-chloro-5-methyl-3- pyridazinamine and 6-chloro-4-methyl-3-pyridazinamine. This material was recrystallized from EtOAc: from the first run 6-chloro-4-methyl-3-pyridazinamine (D4) (0.136 g, 0.95 mmol) was obtained. HPLC (walk-up): rt = 1.21 min. MS: (ES/+) m/z: 287 [dimer+1, 100%] and 289 [dimer+1, 66%]. C5H6ClN3 requires 144. UPLC: rt = 0.33, peak observed: 144 (M+ 1, 100%) and 146 (M+l, 33%). 1H NMR (400 MHz, DMSO-J6) delta ppm: 6.74 (s, 1 H) 6.47 (s, 2 H) 2.18 (s, 3 H). The mother liquors were taken and recrystallized with EtOAc other 3 times to give 6-chloro-5-methyl-3-pyridazinamine (0.136 g, 0.95 mmol). HPLC (walk-up): rt = 0.74 min. MS: (ES/+) m/z: 166 [M+Na, 100%] and 168 [M+Na, 33%]. C5H6ClN3 requires 144. UPLC: rt = 0.32, peak observed: 144 (M+l, 100%) and 146 (M+l, 33%). 1H NMR (400 MHz, DMSO-J6) delta ppm: 7.30 (s, 1 H) 6.44 (s, 2 H) 2.08 (s, 3 H).In a 20 ml microwave flask 3, 6-dichloro-4-methylpyridazine (2.30 g, 14.11 mmol) and a 7 M solution of NH3 in methanol (10.08 ml, 70.6 mmol) were added and heated at 140 C. for 4 h under microwave irradiation. After this time the dark brown solution was evaporated and columned on silica gel (flash master, DCM/MeOH faun 100/0 to 80/20). Collected fractions gave (0.91 g, 6.33 mmol, 45%) of a 2/1 mixture of 6-chloro-5-methyl-3-pyridazinamine and 6-chloro-4-methyl-3-pyridazinamine. This material was recrystallized from EtOAc: from the first run 6-chloro-4-methyl-3-pyridazinamine (D4) (0.136 g, 0.95 mmol) was obtained. HPLC (walk-up): rt=1.21 min. MS: (ES/+) m/z: 287 [dimer+1, 100%] and 289 [dimer+1, 66%]. C5H6CIN3 requires 144. UPLC: rt=0.33, peak observed: 144 (M+1, 100%) and 146 (M+1, 33%). 1H NMR (400 MHz, DMSO-d6) delta ppm: 6.74 (s, 1 H) 6.47 (s, 2H) 2.18 (s, 3H). The mother liquors were taken and recrystallized with EtOAc other 3 times to give 6-chloro-5-methyl-3-pyridazinamine (0.136 g, 0.95 mmol). HPLC (walk-up): rt=0.74 min. MS: (ES/+) m/z: 166 [M+Na, 100%] and 168 [M+Na, 33%]. C5H6CIN3 requires 144. UPLC: rt=0.32, peak observed: 144 (M+1, 100%) and 146 (M+1, 33%). 1H NMR (400 MHz, DMSO-d6) delta ppm: 7.30 (s, 1H) 6.44 (s, 2H) 2.08 (s, 3H).(1a) 3, 6-Dichloro-4-methyl pyridizine (4.2 g, 26 mmol, Alfa) was suspended in aqueous 28% NH4OH (14 mL) in a sealed microwave tube and heated at 155 C. for 1.5 h. The microwave tube was uncapped and allowed to stir at room temperature for 30 min and in an ice bath for 30 min. The solid that crashed out was filtered, washed with ice water, and dried to give a mixture of Step 9.1. 6-Chloro-4-methylpyridazin-3-ylamine and Compound No. 29; (Cis)-2-(4-fluorophenyl)-8-methyl-6-(5-methyl-hexahydropyrrolo[3, 4-c]pyrrol-2(1H)-yl)-3-(1H-pyrrolo[2, 3-b]pyridin-4-yl)imidazo[1, 2-b]pyridazine; Step 1.1 6-Chloro-4-methylpyridazin-3-ylamine and PREPARATION 16; 3-Bromo-6-chloro-7-methylimidazo[1, 2- )]pyridazine a) 6-Chloro-5-methylpyridazin-3-amine (+ 6-chloro-4-methylpyridazin-3-amine) Ammonia (32% solution in water, 54 mL) was added to a solution of 3, 6-dichloro-4- methylpyridazine (5.0 g, 30.67 mmol) in ethanol (25 mL) in a sealed tube. The resulting mixture was stirred at 100 C for 70 hours, cooled down and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (3:2 hexanes/ethyl acetate to 100% ethyl acetate) to yield the title compound (3.8 g, 57%) as a mixture of two isomers which was used in the next step without further purification.LRMS (m/z): 144 (M+1)+.PREPARATION 16 3-Bromo-6-chloro-7-methylimidazo[1, 2-b]pyridazine a) 6-Chloro-5-methylpyridazin-3-amine (+ 6-chloro-4-methylpyridazin-3-amine) Ammonia (32% solution in water, 54 mL) was added to a solution of 3, 6-dichloro-4-methylpyridazine (5.0 g, 30.67 mmol) in ethanol (25 mL) in a sealed tube. The resulting mixture was stirred at 100 ºC for 70 hours, cooled down and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (3:2 hexanes/ethyl acetate to 100% ethyl acetate) to yield the title compound (3.8 g, 57%) as a mixture of two isomers which was used in the next step without further purification. LRMS (m/z): 144 (M+1)+.A solution of compound 3, 6-dichloro-4-methylpyridazine (20.0 g, 122.7 mmol) and ammonium hydroxide in water (86.60 g, 245 mmol) was refluxed for about 30 h. The mixture was concentrated and used in the next step without purificationExample 68 Preparation of Intermediate 69 [0675] [0676] A mixture of 3, 6-dichloro-4-methylpyridazine (333 mg, 2.04 mmol) in 3.3 mL of 28% NH4OH and 2 mL of ethanol was heated at 100 C. in a sealed tube for 48 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting solid was washed with ether and decanted (5×) yielding a light yellow solid (123 mg, 42%) as a 55/45 mixture of A suspension of 3, 6-dichloro-4-methyl-pyridazine (3 g, 18.40 mmol) in concentrated ammonia (20 mL, 1.057 mol) in a sealed vessel was heated to 130 C for 15 h. After cooling to rt, it was diluted with water and filtered. The solid was dried under reduced pressure and used directly in the next step (2.2 g). NMR showed it contained two isomers; 6-chloro-4-methyl-pyridazin-3-amine and a) 2, 8-dimethyl-6-(4 A5, 5-tetramethyl- 1 , 3, 2-dioxaborolan-2-yl)imidazor 1 , 2-blpyridazine In a sealed flask, 3, 6-dichloro-4-methylpyridazine (27 g, 161 mmol) was suspended in aqueous ammonia (25%, 300 mL). The reaction mixture was heated at 110 C for 48 hours (turned into solution after 1 hour). After cooling to room temperature, the reaction was poured into CH2CI2, and the organic phase was separated, dried over Na2S04, and concentrated under vacuum, to give 22.4 g of 6-chloro-4-methyl-pyridazin-3-amine and 6-chloro-5-methyl- pyridazin-3-amine as a mixture of regioisomers which were used directly in the next step. The mixture of regioisomers 6-chloro-4-methyl-pyridazin-3-amine and 6-chloro-5-methyl- pyridazin-3-amine (22.4 g) was suspended in 2-propanol (300 mL). l-bromo-2, 2- dimethoxypropane (36.0 g, 26.6 mL, 193 mmol, 1.2 eq.) and PPTS (2.96 g, 11.6 mmol, 0.0725 eq.) were added, and the resulting solution was heated at 105C overnight. The solvent was removed in vacuo and the residue was taken up in CH2C12 and washed with NaHC03. The organic phases were dried over Na2S04, concentrated in vacuo and the crude light brown solid was chromatographed (EtOAc / Heptane 1/2 -1/1) to give separately 6.1 g of 6-chloro-2, 8- dimethyl-imidazo[l, 2-b]pyridazine MS m/z 182.1 [M+H]+ (21%) as a white solid and 5.9 g of 6- chloro-2, 7-dimethyl-imidazo[l, 2-b]pyridazine MS m/z 182.1 [M+H]+ (20%) as a white solid. A mixture of 6-chloro-2, 8-dimethylimidazo[l, 2-b]pyridazine (0.9 g, 4.96 mmol), 4, 4, 4, , 4, , 5, 5, 5', 5'-octamethyl-2, 2'-bi(l, 3, 2-dioxaborolane) (1.26 g, 4.96 mmol, 1.0 eq.), KOAc (0.97 g, 9.91 mmol) and Pd(dppf)Cl2CH2Cl2 (363 mg, 0.49 mmol) in dioxane ( 50 mL) was degassed and heated under N2 at 110 C. After 15 hours, the mixture was diluted with EtOAc, filtered through celite and concentrated under vacuum to give 2, 8-dimethyl-6-(4, 4, 5, 5- tetramethyl-l, 3, 2-dioxaborolan-2-yl)imidazo[l, 2-b]pyridazine which was used directly in the next step.A suspension of 3, 6-dichloro-4-methylpyridazine (3.38 g, 20.74 mmol) in ammonium hydroxide (55 mL, 1412 mmol) was heated in a reactor at 130 C during for about 16 h. The reaction mixture was cooled to room temperature. A precipitate appeared which was filtered, washed with water and dried under vacuum to give an inseparable mixture of 6-chloro-4-methylpyridazin- -amine and 6-chloro-5- methylpyridazin-3 -amine (ratio 57/43) (2.25 g, 76%). NMR (DMSO-d6, 300MHz, ) delta 7.30 (s, 1H), 6.45 (broad, 2H), 2.08 (s, 3H) and 6.74 (s, 1H), 6.47 (broad, 2H), 2.19 (s, 3H).A solution of compound 3, 6-dichloro-4-methylpyridazine (20.0 g, 122.7 mmol) and ammonium hydroxide in water (86.60 g, 245 mmol) was refluxed for about 30 h. The mixture was concentrated and used in the next step without purificationIn a sealed flask, 3, 6-dichloro-4-methylpyridazine (27 g, 161 mmol) was suspended in aqueous ammonia (25%, 300 mL). The reaction mixture was heated at 110 C for 48 hours (turned into solution after 1 hour). After cooling to room temperature, the reaction was poured into CH2C12, and the organic phase was separated, dried over Na2SO4, and concentrated under vacuum, to give 22.4 g of 6-chloro-4-methyl-pyridazin-3-amine and In a sealed flask, 3, 6-dichloro-4-methylpyridazine (27 g, 161 mmol) was suspended in aqueous ammonia (25%, 300 mL). The reaction mixture was heated at 110 C for 48 hours (turned into solution after 1 hour). After cooling to room temperature, the reaction was poured into CH2C12, and the organic phase was separated, dried over Na2SO4, and concentrated under vacuum, to give 22.4 g of 6-chloro-4-methyl-pyridazin-3-amine and A mixture of 3, 6-dichloro-4-methylpyridazine (10 g, 61.7 mmol) and concentrated NH4OH solution (100 ml) was heated at 135 C in a sealed autoclave for 20 h at 20 bar, cooled to RT, diluted with water (200 mL) and stirred in an ice bath for 2 h. The solid was collected by filtration, washed with water and dried in vacuo to afford a mixture of A solution of 3, 6-Dichloro-4-methyl-pyridazine (3.0 g, 18.40 mmol) in Ammonia (28-30% ; 150 ml_) was heated at 130 C in a pressurised reaction vessel for 16 hrs. The reaction mixture was cooled to ambient temperature and extracted with dichloromethane (10 x 100 ml.) The organic layers were combined, dried (MgSO4), filtered and concentrated to give a mixture of the titled compounds (853 mg; 32%). LCMS: (Method A) RT = 0.45 min; m/z = 144 [M+H]+.1H NMR: (400 MHz, DMSO-d6) delta 2.07 (s, 3H), 2.18 (s, 3H), 6.47 (bs, 2H), 6.49 (bs, 2H), 6.74 (s, 1H), 7.31 (s, 1H).

Molecular Weight:143.57
XLogP3:0.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Exact Mass:143.0250249
Monoisotopic Mass:143.0250249
Topological Polar Surface Area:51.8
Heavy Atom Count:9
Complexity:98.2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes