2-Bromoimidazo[2,1-b][1,3,4]thiadiazole

intermediate 3; 2-Bromo-imidazo[2, 1-b][1, 3, 4]thiadiazole; To a suspension of 2-amino-5-bromo-1 , 3, 4-thiadiazoie (1.65 g, 9.15 mmol) in water (27 mL) was added a water solution of chloroacetaldehyde (50percent wt, 1.7 mL). The mixture was stirred at reflux. After 10 hours, a second addition of chloroacetaldehyde (1.5 eq, 1.7 mL) was done and stirring was continued until disappearance of starting material (20 hours). After cooling, the reaction mixture was neutralized with sodium bicarbonate (sat. aq. solution) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried over sodium sulphate and the solvent evaporated under vacuum. The crude product was triturated with diethyl ether to yield 2-bromo-imidazo[2, 1-b][1 , 3, 4]thiadiazole as a white solid. The mother liquor was purified by flash chromatography (Biotage .(TM)., ethyl acetate:hexane, 3:7 to 7:3) to yield another batch of compound (20percent global yield) as a white solid.Intermediate G; 2-Bromoimidazo[2, 1 -b][1 , 3, 4]thiadiazoleTo a suspension of 5-bromo-1 , 3, 4-thiadiazol-2-amine (60 g, 0.33 mol) in Hintermediate 3; 2-Bromo-imidazo[2, 1-b][1, 3, 4]thiadiazole; To a suspension of 2-amino-5-bromo-1 , 3, 4-thiadiazoie (1.65 g, 9.15 mmol) in water (27 mL) was added a water solution of chloroacetaldehyde (50percent wt, 1.7 mL). The mixture was stirred at reflux. After 10 hours, a second addition of chloroacetaldehyde (1.5 eq, 1.7 mL) was done and stirring was continued until disappearance of starting material (20 hours). After cooling, the reaction mixture was neutralized with sodium bicarbonate (sat. aq. solution) and extracted with dichloromethane (3 x 30 mL). The combined organic layers were dried over sodium sulphate and the solvent evaporated under vacuum. The crude product was triturated with diethyl ether to yield 2-bromo-imidazo[2, 1-b][1 , 3, 4]thiadiazole as a white solid. The mother liquor was purified by flash chromatography (Biotage .(TM)., ethyl acetate:hexane, 3:7 to 7:3) to yield another batch of compound (20percent global yield) as a white solid.Intermediate G; 2-Bromoimidazo[2, 1 -b][1 , 3, 4]thiadiazoleTo a suspension of 5-bromo-1 , 3, 4-thiadiazol-2-amine (60 g, 0.33 mol) in HA mixture of 2-bromoimidazo[2, l-b][l, 3, 4]thiadiazole (1.02 g, 5.00 mmol) and 1- chloropyrrolidine-2, 5-dione (434 mg, 3.25 mmol) in DMF (10 mL) was stirred at room (1622) temperature for 2 h. The mixture was diluted with water and treated with Na2S203. The precipitate was collected, washed with water, dried and chromatographed (silica gel, EtOAc in CH2Cl2 0-30%) to provide 2-bromo-5-chloro-imidazo[2, l-b][l, 3, 4]thiadiazole (706 mg, 59.2%). LC-MS 239.8 [M+H]+, RT 1.22 min.A mixture of 2-bromoimidazo[2, l-b][l, 3, 4]thiadiazole (3.0 g, 14.7 mmol, CAS 1137142-58-5), (1 S)- 1 , 3 -dihydrospiro[indene-2, 4'-piperidin]- 1 -amine (1260) dihydrochloride (4.04 g, 14.7 mmol, Intermediate I) and DIPEA (12.8 mL, 73.5 mmol) in DMF (50.0 mL) was stirred at 100 C for 3 hours. The reaction mixture was used directly in the next step. LC-MS (ESI+) m/z: 326.2 (M+H)+.Intermediate 25; 5-lodo-2-morpholin-4-yl-imidazo[2, 1 -b][1, 3, 4]thiadiazole; A mixture of Intermediate 39; 2- Morpholin-4-yl-imidazo[2, 1 -b][ , 3, 4]thiadiazole; A mixture of 2-bromoimidazo[2, 1 -b][1 , 3, 4]thiadiazole (1.2 g, 5.88 mmol) and morpholine (2.05 mL, 23.52 mmol) was heated under microwave irradiation at 135 C for 5 min. On cooling, DCM was added and the suspension was filtered off and the filtrate was evaporated. The residue was purified by column chromatography (Isolute Flash Si II, DCM:MeOH, 100:0 to 98:2) to give the desired product (2-morpholin-4-yl-imidazo[2, 1 -b][1 , 3, 4]thiadiazole).HPLC-MS (method 4): Rt= 0.56 min, [M+1 ]+ m/z 21 1.1. 1H NMR (300 MHz, CDCI3) delta 7.44 (d, J = 1.4 Hz, 1 H), 7.09 (d, J = 1.5 Hz, 1 H), 3.81 (m, 4H), 3.44 (dd, J = 17.2, 12.2 Hz, 4H).Yield: 93%.Intermediate K2-Bromo-5-nitro-imidazo[2, 1-b][1, 3, 4]thiadiazole; Fuming nitric acid (0.15 mL) was added at 0C to a solution of 2-bromo- imidazo[2, 1-b][1 , 3, 4]thiadiazole (0.200 g, 1 mmol) in cone, sulfuric acid (0.24 mL), and the mixture was stirred for 5h. Ice was added, and stirring was continued for 30 min. The solid was filtered off, washed with cold water and dried to give the title compound (0.244 g; 83%)1H NMR (300 MHz, DMSO) delta 8.55 (s, 1 H) ppm.Intermediate H; 2-bromo-5-iodoimidazo[2, 1 -b][1 , 3, 4]thiadiazoleNIS (3.83 g, 16.2 mmol, 1.1 eq) was added to a solution of 2-bromo-imidazo[2, 1- b][1 , 3, 4]thiadiazole (3.0 g, 14.7 mmol, 1 eq) in dry DMF (50 mL). The mixture was stirred at RT for 4h and then poured into aq. Na2S2O3 (10%) and diluted with EtOAc. The organic phase was washed with water, dried and concentrated to give the desired product (pale brown solid; 4.34 g, yield 89%). 1H (300 MHz, CDCI3): delta/ppm 7.29 (1 H, s).Intermediate C2-Bromo-5-iodoimidazo[2, 1-b][1, 3, 4]thiadiazole; NIS (3.83 g, 16.2 mmol, 1.1 eq) was added to a solution of 2-bromo-imidazo[2, 1- b][1 , 3, 4]thiadiazole (3.0 g, 14.7 mmol, 1 eq) in dry DMF (50 mL). The mixture was stirred at RT for 4h and then poured into aq. Na2S203 (10%) and diluted with EtOAc. The organic phase was washed with water, dried and concentrated to give the desired product (pale brown solid; 4.34 g, yield 89%). 1H (300 MHz, CDCI3): 5/ppm 7.29 (1 H, s).Intermediate 1; 2-bromo-5-iodo-imidazo[2, 1-b][1, 3, 4]thiadiazole; To a solution of 2-bromo-imidazo[2, 1-b][1 , 3, 4]thiadiazole (11 .2 g, 54.89 mmol) in DMF (180 mL) was added N-iodosuccinimide (14.3 g, 60.38 mmol). The reaction mixture was stirred at rt for 3 h. The mixture was poured into a 10% sodium thiosulphate solution and diluted with EtOAc. The resulting suspension was filtered off and rinsed with water to give the desired product (2-bromo-5-iodo- imidazo[2, 1 -b][1 , 3, 4]thiadiazole). The organic layer was dried, filtered and evaporated. The residue was suspended in water and filtered to give the same desired product (15.5 g, 85% yield).1H NMR (300 MHz, DMSO) delta 7.43 (s, 1 H).Intermediate 1; 2-bromo-5-iodo-imidazo[2, 1 -b][1 , 3, 4]thiadiazole; To a solution of 2-bromo-imidazo[2, 1-b][1 , 3, 4]thiadiazole (1 1.2 g, 54.89 mmol) in DMF (180 mL) was added N-iodosuccinimide (14.3 g, 60.38 mmol). The reaction mixture was stirred at rt for 3 h. The mixture was poured into a 10% sodium thiosulphate solution and diluted with EtOAc. The resulting suspension was filtered off and rinsed with water to give the desired product (2-bromo-5-iodo- imidazo[2, 1 -b][1 , 3, 4]thiadiazole). The organic layer was dried, filtered and evaporated. The residue was suspended in water and filtered to give the same desired product (15.5 g, 85% yield).1H NMR (300 MHz, DMSO) 5 7.43 (s, 1 H).Intermediate AE 3-(trifluoromethyl)-5-(imidazo[2, 1-b][1, 3, 4]thiadiazol-2-yl)pyridin-2-amineA solution of Intermediate M; 2-(3, 4-Dimethoxy-pheny.)-imidazo[2, 1-b][1, 3, 4]thiadiazoleA solution of 1.5 g of 2-bromo-imidazo[2, 1-b][1 , 3, 4]thiadiazole were dissolved in 10 ml methanol and 10 ml of propylamine were added to the solution. The resulting mixture was heated in a microwave oven at 175C for 15 min. The resulting suspension was evaporated and dissolved in ethylacetate. It was washed with water, dried with sodium sulphate and evaporated. Silica-gel chromatography with petroleum ether - ethylacetate gave 519 mg of the desired product as solid material. HPLC-MS: [M+H]+ 183Intermediate 30; 2-Bromo-imidazo[2, 1-b][1, 3, 4]thiadiazole-5-suIfonic acid; The starting Intermediate 21; (4-FIuoro-phenyI)-imidazo[2, 1-b][1, 3, 4]thiadiazol-2-yl-amine; A mixture of

Molecular Weight:204.05
XLogP3:1.9
Hydrogen Bond Acceptor Count:3
Exact Mass:202.91528
Monoisotopic Mass:202.91528
Topological Polar Surface Area:58.4
Heavy Atom Count:9
Complexity:122
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes