4-Amino-1,2,5-oxadiazole-3-carboxylic acid

To a stirred suspension of ethyl cyanoacetate (28.3 g, 0.25 mol, 1 eq.) and sodium nitrite (17.3 g, 0.25 mol, 1.0 eq.) in a mixture of EtOH (17 mL) and water (200 mL) was added dropwise 85percent Ha. PREPARATION OF 4-AMINO-1, 2, 5-OXADIAZOLE-3-CARBOHYDRAZIDE (COMPOUND 40) [00293] To a solution of 4-amino-l, 2, 5-oxadiazole-3-carboxylic acid (0.50 g, 3.87 mmol) in methanol (30 mL) was bubbled with HCI (gas). The mixture was heated to gentle reflux for 8 h. Methanol was then removed under vacuum to give the crude product as pale yellow oil. To this residue was added diethyl ether (30 mL) and stirred for 30 min. The resulting precipitate was filtered to give desired product 39 (0.50 g, 91 % yield) as white solid. It was used directly in next step without further purification. To a solution of 39 (0.15 g, 1.05 mmol) in methanol (10 mL), was added hydrazine hydrate (0.08 g, 1.57 mmol), the mixture was heated to gentle reflux. After 15 h, the solvent was removed completely under vacuum to give 40 (0.09 g, 60% yield) as white solid. XH NMR (500 MHz, c '-acetone) delta ppm 9.50 (brs, 1H), 5.76 (s, 2H), 4.50 (brs, 2H); 1 C NMR (125 MHz, c '-acetone) delta ppm 157.02, 156.06, 140.00; HRMS (ESI) Calcd for C3H5N5O2 (M + H)+ 144.0516, found 144.0519.The compound 0069-1 (2.50 g, 19.37 mmol, 1.00 eq) was dissolved in N, N-dimethylformamide (60.00 mL), then a compound BB-1-4 (3.68 g, 19.37 mmol, 1.00 eq), HATU (8.84 g, 23.24 mmol, 1.20 eq), and diisopropylethylamine (5.01 g, 38.74 mmol, 6.77 mL, 2.00 eq) were sequentially added. The reaction solution was allowed to react at 25 C. for 1 hour. The reaction solution turned yellow. With LCMS showing completion of reaction, 240 mL of water was added to the resulting mixture, followed by filtration. A filter cake was washed with water (20 mL*3), and naturally dried to obtain a gray solid product 0069-2 (5.50 g, yield: 92.43%, purity: 98%) which was directly used for reaction in a next step. MS (ESI) m/z: 301, 303 [M+H]+.In a two necked R.B. flask fitted with thermometer pocket and nitrogen inlet, TBTU (4.75 g, 14.8 mmol) and N, /V-diisopropylethylamine (2.6 mL, 14.8 mmol) were added to a stirred solution of 3-aminoisonicotinamide (1 .7 g, 12.4 mmol) and 4-amino-1 , 2, 5-oxadiazole-3- carboxylic acid (1 .92 g, 14.8 mmol) in DMF (40 mL) at 25-30 C. Resulting reaction mixture was stirred for 72 h at 25-30 C. Reaction mixture was poured over water (200 mL) and precipitated solid was collected by filtration. Washed with water (100 mL). Purification was done by trituration by using 20% ethyl acetate in n-Hexane to get 4-amino-N-(4- carbamoylpyridin-3-yl)-1 , 2, 5-oxadiazole-3-carboxamide (0.84 g, 27.45%) as Off-white solid 1 H-NMR (400 MHz, DMSO-d6): delta 12.60 (s, 1 H, Exchangeable with D20), 9.70 (s, 1 H), 8.64 (s, 1 H, Exchangeable with D20), 8.52 (d, J = 4.4Hz, 1 H), 8.81 (s, 1 H, Exchangeable with D20), 7.80 (d, J = 4.8 Hz, 1 H), 6.25 (s, 2H, Exchangeable with D20). LCMS (m/z [M+H]+): 249.1 , Rt2=1.312 min.

Molecular Weight:129.07
XLogP3:-0.2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:1
Exact Mass:129.01744097
Monoisotopic Mass:129.01744097
Topological Polar Surface Area:102
Heavy Atom Count:9
Complexity:128
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes