ETHYL3-METHYL-1,2,4-OXADIAZOLE-5-CARBOXYLATE

Scheme 11 : Synthesis of ethyl 3-methyl-l, 2, 4-oxadiazole-5-carboxylate 2.2mTo a solution of (E)-N'-hydroxyacetimidamide 2.0m (1.0 g, 13.50 mmol, 1 eq.) and pyridine (4.35 mL, 54.0 mmol, 4 eq.) in dry DCM (40 mL) was added at RT ethyloxalyl chloride (2.4 g, 18.0 mmol, 1.3 eq.). The solution was stirred at reflux for 14 hours. The reaction mixture was cooled down to RT and quenched with NHTo a solution of ethyl 2-chloro-2-oxoacetate (1 g, 13.5 mmol) and pyridine (4.27 g, 54 mmol, 4.36 mL) in dichloromethane (40 mL) was added at 15-20C N'-hydroxyacetimidamide (2.40 g, 17.5 mmol, 1 .96 mL). The solution was stirred at 50C for 14 hours. The reaction mixture was cooled and quenched with saturated aqueous NH4CI (30 mL). The aqueous phase was extracted with dichloromethane (2chi50 mL). The organic phases were combined, washed with saturated aqueous NaHC03(50 mL), dried over MgS04, filtered and concentrated under reduced pressure to give ethyl 3-methyl-1 , 2, 4-oxadiazole-5-carboxylate (2.80 g, 44% yield).To a solution of ethyl 2-chloro-2-oxoacetate (1 g, 13.5 mmol) and pyridine (4.27 g, 54 mmol, 4.36 mL) in dichloromethane (40 mL) was added at 15-20C N'-hydroxyacetimidamide (2.40 g, 17.5 mmol, 1.96 mL). The solution was stirred at 50C for 14 hours. The reaction mixture was cooled and quenched with saturated aqueous NH4CI (30 mL). The aqueous phase was extracted with dichloromethane (2 c 50 mL). The organic phases were combined, washed with saturated aqueous NaHCC>3 (50 mL), dried over MgS04, filtered and concentrated under reduced pressure to give ethyl 3-methyl-l, 2, 4-oxadiazole-5-carboxylate (2.80 g, 44% yield).To a solution of 161 ethyl 2-chloro-2-oxoacetate (1 g, 13.5 mmol) and 162 pyridine (4.27 g, 54 mmol, 4.36 mL) in 68 dichloromethane (40 mL) was added at 15-20 C. 163 N?-hydroxyacetimidamide (2.40 g, 17.5 mmol, 1.96 mL). The solution was stirred at 50 C. for 14 hours. The reaction mixture was cooled and quenched with saturated aqueous NH4Cl (30 mL). The aqueous phase was extracted with dichloromethane (2×50 mL). The organic phases were combined, washed with saturated aqueous NaHCO3 (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give 164 To a solution of ethyl 2-chloro-2-oxoacetate (1 g, 13.5 mmol) and pyridine (4.27 g, 54 mmol, 4.36 mL) in dichloromethane (40 mL) was added at 15-20C N'-hydroxyacetimidamide (2.40 g, 17.5 mmol, 1.96 mL). The solution was stirred at 50C for 14 hours. The reaction mixture was cooled and quenched with saturated aqueous NH4CI (30 mL). The aqueous phase was extracted with dichloromethane (2 c 50 mL). The organic phases were combined, washed with saturated aqueous NaHCC>3 (50 mL), dried over MgS04, filtered and concentrated under reduced pressure to give ethyl 3-methyl-l, 2, 4-oxadiazole-5-carboxylate (2.80 g, 44% yield).Experiment 21b; The ethyl ester was prepared according to the ref: /. Med. Chem. 2004, 47 (14), 3642-3657. It was further reduced by DIBAL-H to give the corresponding aldehyde 13a.To a solution of ethyl 3-methyl-1 , 2, 4-oxadiazole-5-carboxylate (2.10 g, 13.5 mmol) in THF (10 mL) and ethanol (10 mL) was added NaBH4(1 .02 g, 26.9 mmol) at 0C. The mixture was stirred at 0C for 1 hour. The mixture was quenched with saturated aqueous NH4CI , and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and filtered; the filtrate was dried over Na2S0 and concentrated in vacuo to give (3-methyl-1 , 2, 4- oxadiazol-5-yl)methanol (800 mg, 52% yield).To a solution of ethyl 3-methyl-l, 2, 4-oxadiazole-5-carboxylate (2.10 g, 13.5 mmol) in THF (10 mL) and ethanol (10 mL) was added NaBH4 (1.02 g, 26.9 mmol) at 0C. The mixture was stirred at 0C for 1 hour. The mixture was quenched with saturated aqueous NH4CI , and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and filtered; the filtrate was dried over Na2S04 and concentrated in vacuo to give (3-methyl-l, 2, 4-oxadiazol-5-yl)methanol (800 mg, 52% yield).To a solution of 164 To a solution of ethyl 3-methyl-l, 2, 4-oxadiazole-5-carboxylate (2.10 g, 13.5 mmol) in THF (10 mL) and ethanol (10 mL) was added NaBH4 (1.02 g, 26.9 mmol) at 0C. The mixture was stirred at 0C for 1 hour. The mixture was quenched with saturated aqueous NH4CI , and concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and filtered; the filtrate was dried over Na2S04 and concentrated in vacuo to give (3-methyl-l, 2, 4-oxadiazol-5-yl)methanol (800 mg, 52% yield).3-methyl - [1, 2, 4] aqueous solution of potassium hydroxide in ethanol solution (50 mL) of oxadiazole-5-carboxylic acid ethyl ester (9.45g) (4.0g) and (20 mL) was added at room temperature and the reaction mixture was stirred for 2 hours.The solvent was distilled off under reduced pressure, the residue acetonitrile was added to the solids were collected by filtration and dried 3-methyl - [1, 2, 4] oxadiazol-5-carboxylic acid potassium salt (9.38 g) It was obtained.The resulting 3-methyl - [1, 2, 4] oxadiazole in acetonitrile-5-carboxylic acid potassium salt (2.8 g) (60 mL) in oxalyl chloride (1.4 mL) and DMF (1 drop) It was added and the reaction mixture was stirred for 2 hours at room temperature.The reaction mixture was added dropwise under ice-cooling in methylene chloride solution (90 mL) of the compound obtained in Reference Example 7 (2.44g) and triethylamine (3.8 mL), and stirred at room temperature for 2 hours.Water was added to the reaction mixture, the mixture was extracted twice with chloroform.The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated.The residue was purified by silica gel column chromatography, and purified by (solvent: hexane / ethyl acetate = 70 / 30-20 / 80) to give the title compound (1.68 g).MS (ESI) M / Z; 471 [M Tasu H]TasuScheme 11 : Synthesis of ethyl 3-methyl-l, 2, 4-oxadiazole-5-carboxylate 2.2mTo a solution of (E)-N'-hydroxyacetimidamide 2.0m (1.0 g, 13.50 mmol, 1 eq.) and pyridine (4.35 mL, 54.0 mmol, 4 eq.) in dry DCM (40 mL) was added at RT ethyloxalyl chloride (2.4 g, 18.0 mmol, 1.3 eq.). The solution was stirred at reflux for 14 hours. The reaction mixture was cooled down to RT and quenched with NH4C1 sat. (30 mL). The aqueous phase was extracted with DCM (2 x 50 mL). The organic phases were combined, washed with NaHC03 sat. (50 mL), dried over MgS04, filtered and concentrated under reduced pressure to give 2.2m as yellow oil (1.32 g, 8.45 mmol, 63 %) which was used in the next step without further purification. LCMS: P = 92 , retention time = 2.0 min, (M+H)+: 157.A mixture of compound IM1 (160 mg, 1 mmol) and (c) Preparation of N-(2-chlorophenyl)-3 -methyl- 1, 2, 4-oxadiazole-5-carboxamide 6:To a mixture of ethyl 3-methyl-l, 2, 4-oxadiazole-5-carboxylate 5 (1.0 g, 6.4 mmol) and 2- chlorobenzenamine (1.23 g, 9.6 mmol) in toluene (20 mL) was added AlMe3 (2.0 M 4.8 mL, 9.6 mmol) dropwise. The reaction mixture was stirred under reflux overnight, treated with IN HC1 (5 mL) and ethyl acetate (50 mL). The organic phase was dried and concentrated. The residue was purified by column chromatography eluting with hexane:ethyl acetate (1 :3) to afford N-(2- chlorophenyl)-3-methyl-l, 2, 4-oxadiazole-5-carboxamide 6. Yield: 1.0 g, 66%.1H-NMR (300 Hz, CDCls) delta (ppm): 9.98 (s, 0.5 H), 9.38 (s, 0.5 H), 8.52-8.43 (m, 1 H), 7.48- 7.38 (dd, 1 H), 7.40-7.32 (m, 1 H), 7.22-7.13 (m, 1 H), 2.56 (s, 3 H).PREPARATION 1

Molecular Weight:156.14
XLogP3:1.1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:156.05349212
Monoisotopic Mass:156.05349212
Topological Polar Surface Area:65.2
Heavy Atom Count:11
Complexity:151
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes