Ethyl5-bromo-1,3,4-thiadiazole-2-carboxylate

To a stirred solution of compound 59 (21 g, 121.38 mmol) in ACN (400 mL), CuBrA 500 mL (three neck) round-bottom flask with a stir bar, needle inlet, and a gas outlet to a trap containing a 10percent solution of NaStep l:5-Bromo-[l, 3, 4]thiadiazole-2-carboxylic acid ethyl ester (3_39_2) [00332] CuBrStep 2: ethyl 5-bromo-l, 3, 4-thiadiazole-2-carboxylate ter-BuONOTo a stirred solution of ethyl 5-amino-l, 3, 4-thiadiazole-2-carboxylate (3.1 g, 17.8 mmol) in acetonitrile (50 mL) at room temperature was added copper (II) bromide (7.95 g, 35.6 mmol) and the mixture was stirred for 20 min. Tertiary butyl nitrite (3.67 g, 35.63 mmol) was then added drop wise for 10 min, and the reaction mixture was heated to 60°C for 30 min. The reaction mixture was concentrated under reduced pressure, diluted with water (300 mL), and then extracted with ethyl acetate (500 m:). The organic layer was separated and dried over anhydrous sodium sulphate, and evaporated to afford ethyl 5-bromo-l, 3, 4-thiadiazole-2-carboxylate as a brown solid (3.0 g, 74percent yield). Under the ice bath, Add A hydrogen chloride/ethyl acetate solution (4N, 3 mL) was added to a solution of tert-butyl (3S, 4R)-4-{[(4-chloro-5-ethyl-lH-imidazol-2- yl)carbonyl]amino}-3-methoxypiperidine-l-carboxylate (1.0 g) obtained in Step 4 in ethyl acetate (3 mL), and the mixture was allowed to stand at room temperature for 30 minutes. The solvent was evaporated under reduced pressure to obtain crude 4-chloro-N-[(3S, 4R)-3-methoxypiperidin- 4-yl]-5-ethyl-lH-imidazole-2-carboxamide hydrochloride as a colorless amorphous solid. A suspension of the crude 4-chloro-N-[(3S, 4R)-3- methoxypiperidin-4-yl]-5-ethyl-lH-imidazole-2-carboxamide hydrochloride obtained above, ethyl 5-bromo-l, 3, 4-thiadiazole-2- carboxylate (0.66 g) and sodium bicarbonate (1.05 g) in DMF (40 mL) was stirred at 70 C for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column (ethyl acetate-hexane) to obtain title compound (1.4 g) as a colorless solid. Mass (ESI): m/z 443 (M+H)+.A mixture of 4-(((l S, 4S, 5R)-2-azabicydo[2.2.l ]heptan-5-yloxy)methyl)-5-20 cyclopropyl-3-(2, 6-dichlorophenyl)isoxazole hydroiodide salt 12dd (214 mg, 0.52 mmo, 1equiv.), A hydrogen chloride/ethyl acetate solution (4N, 3 ml_) was added to a solution of fe/f-butyl (3S, 4R)-4-{[(4-chloro-5-ethyl-1 H-imidazol-2- yl)carbonyl]amino}-3-methoxypiperidine-1 -carboxylate (1 .0 g) obtained in Step 4 in ethyl acetate (3 ml_), and the mixture was allowed to stand at room temperature for 30 minutes. The solvent was evaporated under reduced pressure to obtain crude 4-chloro-/V-[(3S, 4R)-3-methoxypiperidin-4-yl]-5-ethyl- 1 H-imidazole-2-carboxamide hydrochloride as a colorless amorphous solid. A suspension of the crude 4-chloro-/V-[(3S, 4R)-3-methoxypiperidin-4- yl]-5-ethyl-1 H-imidazole-2-carboxamide hydrochloride obtained above, ethyl 5-bromo-1 , 3, 4-thiadiazole-2-carboxylate (0.66 g) and sodium bicarbonate (1 .05 g) in DMF (40 ml_) was stirred at 70 C for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column (ethyl acetate-hexane) to obtain title compound (1 .4 g) as a colorless solid. Mass (ESI): m/z 443 (M+H)+.A hydrogen chloride/ethyl acetate solution (4N, 30 mL) was added to a solution of fe/f-butyl (3S, 4R)-4-{[(4-chloro-5-ethyl-1 H-imidazol-2- yl)carbonyl]amino}-3-ethoxypiperidine-1 -carboxylate (3.4 g, 8.5 mmol) obtained in Step 2 in dichloromethane (20 mL), and the mixture was allowed to stand at room temperature for 30 minutes. The solvent was evaporated under reduced pressure to obtain crude 4-chloro-/V-[(3S, 4R)-3- ethoxypiperidin-4-yl]-5-ethyl-1 /-/-imidazole-2-carboxamide hydrochloride as a colorless amorphous solid. A solution of the crude 4-chloro-/V-[(3S, 4R)-3-ethoxypiperidin-4-yl}-5- ethyl-1 H-imidazole-2-carboxamide hydrochloride obtained above, ethyl 5- bromo-1 , 3, 4-thiadiazole-2-carboxylate (2.01 g, 8.5 mmol) and sodium bicarbonate (1 .68 g, 20 mmol) in dimethylacetamide (40 mL) was stirred at 70C for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column (ethyl acetate-hexane) to obtain the title compound (3.75 g, 97%) as a colorless solid. 1 H-NMR (400MHz, DMSO-De) delta ppm: 7.67 (1 H, d, J = 8.59 Hz), 4.35 (2H, q, J = 7.16 Hz), 4.26-4.17 (2H, m), 4.05-3.97 (1 H, m), 3.70-3.40 (5H, m), 2.55 (2H, q, J = 7.45 Hz), 1 .95-1 .88 (1 H, m), 1 .72-1 .68 (1 H, m), 1 .31 (3H, t, J= 7.16 Hz), 1 .14 (3H, t, J = 7.45 Hz), 1 .03 (3H, t, J = 7.16 Hz).Step 3: (5-bromo-l, 3, 4-thiadiazol-2-yl)methanol A solution of ethyl 5-bromo-l, 3, 4-thiadiazole-2-carboxylate (3.0 g, 12.6 mmol) in methanol (50 mL) was cooled to 0C and then sodium borohydride (1.40 g, 38.0 mmol) was added slowly. The reaction mixture was allowed to stir for 16 hours at room temperature. The reaction mixture was quenched with acetic acid (3 mL), extracted with ethyl acetate (200 mL), the organic layer was washed with sodium bicarbonate solution (20 mL) followed by brine solution (10 mL), the organic layer was separated, dried over sodium sulphate and evaporated under reduced pressure to obtain crude product. The crude product was purified by a Biotage Isolera One column (using 25% ethyl acetate and hexane) to give (5-bromo-l, 3, 4-thiadiazol-2- yl)methanol as a white solid (1.8 g, 73% yield). 1H NMR (400 MHz, DMSO-d6): ' 6.31 (t, 3H), 4.85 (d, 2H); LC-MS m/z calcd for [M+H]+ 194.91, found 195.0.Step 1: (5-bromo-l, 3, 4-thiadiazol-2-yl)methanol A solution of ethyl 5-bromo-l, 3, 4-thiadiazole-2-carboxylate (3.0 g, 12.65 mmol) [prepared as described in Jean-Philippe, International Patent Publication No. WO-2011/011872] in methanol (50 mL) was cooled to 0C and sodium borohydride (1.405 g, 37.97 mmol) slowly added and the reaction mixture was allowed to stir for 16 hours at room temperature. The reaction mixture was quenched with acetic acid (3 mL), extracted with ethyl acetate (200 mL), and the organic layer washed with sodium bicarbonate solution (20 mL) and then brine solution (10 mL). The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure to obtain crude product. The crude product was purified by Biotage IsoleraOne column (using 25% ethyl acetate and hexane) to give (5-bromo-l, 3, 4-thiadiazol-2- yl)methanol as white solid (1.8 g, 73% Yield). XH NMR (400 MHz, DMSO-d6): delta 6.31 (t, 3H), 4.85 (d, 2H); LC-MS m/z calculated for [M+H]+ 194.9, found 195.0.To a stirred solution of compound 60 (25 g, 105.96 mmol) in MeOH (250 mL) at 0C, NaBH4 (12 g, 317.20 mmol) was added portion wise and stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with acetic acid (5 mL); diluted with water and extracted with ethyl acetate. The combined organic layers were washed with sat. NaHCO3 solution; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain crude. The crude was purified through silica gel column chromatography using 15% EtOAc/ hexanes to afford compound 61 (15 g, 73%) as yellow solid. TLC: 40% EtOAc/ hexanes (Rf: 0.3); 1H NMR (400 MHz, DMSO-d6): delta 6.39 (t, J= 6.0 Hz, 1H), 4.85-4.83 (s, 2H); LCMS Calculated for C3H3BrN2OS: 193.91; Observed: 194.90 (M + 1)+.A 500 mL (two neck) round-bottom flask with a stir bar, gas inlet, and septum was charged with 5-bromo-[l, 3, 4]thiadiazole-2-carboxylic acid ethyl ester (8.91 g, 37.59 mmol), CH2CI2 (100 mL), and methanol (50 mL). The solution was cooled to - 74C (internal, acetone/C02 bath) and NaBH (4.27 g, 1 12.8 mmol, 3 equiv.) was added slowly. The reaction mixture was allowed to warm to room temperature over 4 hours, during which time gas evolution was observed and the solution became yellow in color. The reaction mixture was diluted with EtOAc and washed with H20 and Brine. The crude product was filtered through a Si02 plug (Yamazen, Large load column, 0-50% EtOAc/Hexanes). Recrystallization from TBME (-30 mL) provided (5- Bromo-[l, 3, 4]thiadiazol-2-yl)-methanol (4.22 g, 58%) as yellow needles.Concentration of the mother liquor and recrystallization from TBME provided additional product.Step 2:5-Bromo-[l, 3, 4]thiadiazole-2-carboxylic acid amide (3_39_3) [00334] NH4OH (50 % aq solution, 6.45 mL) was added to a solution of compound 3_39_2 (7.56 g, 31.8 mol) in 70 mL of tetrahydrofuran, and the mixture was stirred at room temperature for 16 h and concentrated to give a solid, which was triturated with ether, filtered, and dried to give compound 3_39_3 (6.5 g, 98 % yield) as a yellow solid. [00335] NMR (400 MHz, DMSO-rf6): delta = 8.26 (br. s., 1 H), 8.64 (br. s., 1 H).Step 2: 5-Bromo-1, 3, 4-thiadiazole-2-carboxamide To a solution of To a solution of ethyl 5-bromo-l, 3, 4- thiadiazole-2-carboxylate in THF (1.1 M) at room temperature was added concentrated NH4OH (2.9 equiv). The mixture was stirred at room temperature overnight and a precipitate appeared in the aqueous layer. Volatile solvent was removed in vacuo. The mixture was diluted with water and the precipitate was collected, washed with water and dried under vacuum to give the title compound. lH NMR (400 MHz, acetone-J6): delta 7.99 (s, IH), 7.55 (s, IH).To a solution of ethyl 5-bromo-l, 3, 4- thiadiazole-2-carboxylate in THF (1.1 M) at room temperature was added concentrated NH4OH (2.9 equiv). The mixture was stirred at room temperature overnight and a precipitate appeared in the aqueous layer. Then the volatile solvent was removed in vacuo. The resulting mixture was diluted with water and the precipitate was collected, washed with water and dried under vacuum to give the title compound.Step 2 5-Bromo-l, 3, 4-thiadiazole-2-carboxamideTo a solution of ethyl 5-bromo-l , 3, 4-thiadiazole-2-carboxylate in THF (1 1 M) at room temperature was added concentrated NH4OH (2 9 equiv) The mixture was stirred at room temperature overnight and a precipitate appeared in the aqueous layer Volatile solvent was removed under diminished pressure The mixture was diluted with water and the precipitate was collected, washed with water and d'ed under vacuum to give the title compound 1 H NMR (400 MHz, acetone-^) delta 7 99 (s, IH), 7 55 (s, IH)To a stirred solution of compound 59 (21 g, 121.38 mmol) in ACN (400 mL), CuBr2 (53.3 g, 239.01 mmol) was added and stirred at room temperature for 15 min. To this solution, tert- butyl nitrite (24.65 g, 239.04 mmol) was added drop wise over a period of 20 min. The resulting reaction mixture was stirred at room temperature for 30 min. and then heated at 60 C for 30 min. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water; ethyl acetate and filtered through Celite bed. The organic layer was separated; washed with brine; dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound 60 (25 g, 87.40percent) as a yellow solid. TLC: 20percent EtOAc/hexane (Rf: 0.7); 1H NMR (400 MHz, DMSO-d6): delta 4.45-4.40 (m, 2H), 1.34 (t, J= 6.8 Hz, 3H).A 500 mL (three neck) round-bottom flask with a stir bar, needle inlet, and a gas outlet to a trap containing a 10percent solution of Na2S203 was charged with CuBr (1.24g, 8.67 mmol, 0.1 equiv.) and HBr (48percent aqueous solution, 108 mL). The purple solution was cooled to 3°C (internal, ice bath), to which was added portion- wise a solid mixture of 5-amino-[l, 3, 4]thiadiazole-2-carboxylic acid ethyl ester (15.0 g, 86.6 mmol) and sodium nitrite (27.0 g, 391.3 mmol, 4.5 equiv.) over the course of 30 min. The reaction mixture was allowed to warm to room temperature for 2 h 15 min. The reaction mixture was diluted with CH2C12 and 10percent aqueous Na2S203 and the layers were separated. The aqueous layer was extracted 3 times with CH2C12. The combined organic layers were washed with Brine, dried over MgS04, and concentrated. The crude product was purified by column chromatography (ISCO XL, 330g Si02 column, 20-25percent EtOAc/Hexanes) to provide an off-white solid that was triturated with 5percent EtOAc/Hexanes. Filtration provided 5-bromo-[l , 3, 4]thiadiazole-2-carboxylic acid ethyl ester (14.5 g, 71percent) as white needles. Concentration and trituration of the mother liquor provided an additional product (2.3 g, 11percent).Step l:5-Bromo-[l, 3, 4]thiadiazole-2-carboxylic acid ethyl ester (3_39_2) [00332] CuBr2 (18.06 g, 80.1 mmol) was added to a suspension of 5-amino- [l, 3, 4]thiadiazole-2-carboxylic acid ethyl ester 3_39_1 (7 g, 40.5 mmol) in 150 mL of acetonitrile, the mixture was stirred for 15 min, t-BuONO (9.6 mL, 80.1 mmol) was added over 20 min., and the mixture was heated at 60°C for 0.5 h. Water and ethyl acetate were added, the mixture was stirred until the dark color disappeared and filtered through celite, and the organic layer was washed with brine, dried over Na2S04, filtrated and concentrated to give compound 3_39_2 (7.56 g, 79 percent yield) as a yellow solid. [00333] NMR (400 MHz, DMSO-d6): delta = 1.32 (t, J = 7.14 Hz, 3 H), 4.41 (q, J = 7.30 Hz, 2 H);Step 2: ethyl 5-bromo-l, 3, 4-thiadiazole-2-carboxylate ter-BuONOTo a stirred solution of ethyl 5-amino-l, 3, 4-thiadiazole-2-carboxylate (3.1 g, 17.8 mmol) in acetonitrile (50 mL) at room temperature was added copper (II) bromide (7.95 g, 35.6 mmol) and the mixture was stirred for 20 min. Tertiary butyl nitrite (3.67 g, 35.63 mmol) was then added drop wise for 10 min, and the reaction mixture was heated to 60°C for 30 min. The reaction mixture was concentrated under reduced pressure, diluted with water (300 mL), and then extracted with ethyl acetate (500 m:). The organic layer was separated and dried over anhydrous sodium sulphate, and evaporated to afford ethyl 5-bromo-l, 3, 4-thiadiazole-2-carboxylate as a brown solid (3.0 g, 74percent yield). XH NMR (400 MHz, CDC13): ' 4.53-4.51 (m, 2H), 1.45-1.43 (m, 3H); LC-MS m/z calcd for [M+H]+ 238.92, found 238.9.Step 1: Ethyl 5-bromo-1, 3, 4-thiadiazole-2-carboxylate To a suspension of ethyl 5-amino-1, 3, 4-thiadiazole-2-carboxylate (10 g, 58 mmol) in CH3CN (180 mL) was added CuBr2 (25.7 g, 115 mmol). The mixture turned dark green and was further stirred for 15 min at room temperature. t-BuONO, 90percent (13.8 mL, 115 mmol) was added dropwise over 15-20 min. The mixture became slightly warm and gas was evolved after 5 min and then throughout the addition. After completion of the addition and gas evolution subsided, the mixture was heated at 60° C. for 30 min. Solvent was then evaporated in vacuo. Water and EtOAc were added and the mixture was agitated in the flask until the dark green color disappeared. The organic phase became light brown and the aqueous was green with insoluble material. The whole mixture was filtered through celite and washed with EtOAc. The EtOAc layer was separated, washed with dilute brine solution, dried (Na2SO4) and concentrated to give the title compound. 1H NMR (400 MHz, acetone-d6): delta4.52 (q, 2H), 1.43 (t, 3H).To a suspension of ethyl 5-amino-l, 3, 4- thiadiazole-2-carboxylate in CH3CN (0.32 M) was added CuBr2 (2 equiv). The mixture turned dark green and was stirred for 15 min at room temperature. t-BuONO, 90percent (2 equiv) was added dropwise over 15 - 20 min. The mixture became slightly warm and gas evolved after about 5 min and then throughout the addition. After completion of the addition and after gas evolution subsided, the mixture was heated at 60 °C for 30 min. Solvent was then evaporated in vacuo. Water and EtOAc were added and the mixture was stirred until the dark green color disappeared. The organic phase became light brown and the aqueous phase was green with insoluble material. The entire mixture was filtered through Celite.(TM). and washed with EtOAc. The EtOAc layer was separated, washed with diluted brine, dried (Na2SO4) and concentrated to give the title compound. lH NMR (400 MHz, acetone-^): delta 4.52 (q, 2H), 1.43 (t, 3H).To a suspension of ethyl 5-amino- l, 3, 4-thiadiazole-2-carboxylate in CH3CN (0.32 M) was added CuBr2 (2 equiv). The mixture turned dark green and was stirred for 15 min at room temperature. Then /-BuONO (2 equiv, 90percent) was added dropwise over 15 - 20 min. The mixture became slightly warm and gas evolved after about 5 min and then throughout the addition. After completion of the addition and after gas evolution subsided, the mixture was heated at 60 °C for 30 min. Solvent was then evaporated in vacuo. Water and EtOAc were added and the mixture was stirred until the dark green color disappeared. The mixture was filtered through Celite.(TM). and washed with EtOAc. The EtOAc layer was separated, washed with diluted brine, dried (Na2SO4) and concentrated to give the title compound. lH NMR (400 MHz, acetone-t/6): delta 4.52 (q, 2H), 1.43 (t, 3H).Step 1 Ethyl 5-bromo-l , 3, 4-thiadiazole-2-carboxylateTo a suspension of ethyl 5-ammo-l , 3, 4-thiadiazole-2-carboxylate in CH3CN (0 32 M) was added CuBr2 (2 equiv) The mixture turned dark green and was stirred for 15 mm at room temperature ^-BuONO, 90percent (2 equiv) was added dropwise over 15 - 20 mm The mixture became slightly warm and gas was evolved after about 5 min and then throughout the addition After completion of the addition and gas evolution subsided, the mixture was heated at 60 0C for 30 mm Solvent was then evaporated under diminished pressure Water and EtOAc were added and the mixture was stirred until the dark green color disappeared The organic phase became light brown and the aqueous phase was green with insoluble material The entire mixture was filtered through celite and washed with EtOAc The EtOAc layer was separated, washed with diluted bpine, dpied (Na2SO4) and concentrated to give the title compound lH NMR (400 MHz, acetone-d) delta 4 52 (q, 2H), 1 43 (t, 3H)

Molecular Weight:237.08
XLogP3:1.9
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:235.92551
Monoisotopic Mass:235.92551
Topological Polar Surface Area:80.3
Heavy Atom Count:11
Complexity:157
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes