2-(CHLOROMETHYL)-5-METHYL-1,3,4-OXADIAZOLE

Potassium hydroxide (2.00 g) was added to a solution of 6-bromo-2-methyl-1H-imidazo[4, 5-b]pyridine (5.80 g), To a solution of tert-butyl (2S, 4S)-4-hydroxy-2-methyl-piperidine-1-carboxylate (0.5 g, 2 mmol) in N, N-dimethylformamide (5 mL) under nitrogen at room temperature is added portionwise sodium tert-butoxide (0.92 g, 9.28 mmol). The resulting reaction mixture is stirred at room temperature for 40 min. The reaction mixture is cooled to 0 C. and To the mixture of A-4 (200 mg, 0.68 mmol) and 2-(chloromethyl)-5 -methyl- 1, 3, 4-oxadiazole (179.6 mg, 1.35 mmol) in ACN (3 mL) was added K2C03 (187.27 mg, 1.35 mmol) and the mixture was stirred at 20 C for 16 hours. The mixture was diluted with H20 (20 mL), and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2SC>4, filtered and the filtrate was concentrated to give the crude product, which was purified by Prep-HPLC (Phenomenex Gemini (150 mm x 25mm, 10 muiotaeta); A = H20 (0.05% NH4OH) and B = CH3CN); 58-68% B over 8 minutes) to afford Compound 51 (52.03 mg, 0.13 mmol) as a solid. XH NMR (MeOD-c 400MHz) deltaH = 7.70 (d, 2H), 7.52 (d, 1H), 7.48 - 7.44 (m, 1H), 7.40 - 7.34 (m, 3H), 5.40 (s, 2H), 2.52 (s, 3H). LCMS Rt = 1.18 min using Method A, MS ESI calcd. for Ci8Hi3F3N304 [M+H]+ 392.1, found 391.9.A solution of 4-(6-(3 , 6-diazabicyclo[3. 1.1 ]heptan-3 -yl)pyridin-3 -yl)-6-(2-hydroxy-2- methylpropoxy)pyrazolo[ 1, 5 -a]pyridine-3 -carbonitrile dihydrochloride (Intermediate P43; 20 mg, 0.0419 mmol) in DMSO (837.9 tL) was treated with C52CO3(s) (54.60 mg, 0.1676 mmol ) and To a solution of 6-(4-fluorophenyl)-3-trityl-1, 3-dihydro-2H-imidazo[4, 5-b]pyridin-2-one (205 mg, 0.44 mmol) in DMF (4 mL) was added NaH (60% dispersion in mineral oil, 23 mg, 0.57 mmol) in one portion at room temperature. The reaction was stirred until gas evolution had ceased, then 2-Chloromethyl-5-methyl-1, 3, 4-oxadiazole (100 mg, 0.758 mmol), 3, 7-dimethyl-1H-purine-2, 6(3H, 7H)-dione(136 mg, 0.758 mmol), potassium iodide (12.0 mg, 0.0758 mmol) and potassium carbonate (209 mg, 1.52 mmol) were dissolved in anhydrous N, N-dimethylformamide (3 mL). The reaction was heated to 120C and reacted for 3 hours. The reaction solution was cooled to 20C, filtered and purified by preparative HPLC to give 3, 7-dimethyl-1-((5-methyl-1, 3, 4-oxadiazol-methyl)-1H-purine-2, 6(3H, 7H)-dione (30.0 mg) with a yield of 34%. 1H NMR: (400 MHz, Methonal-d4) delta 7.94(s, 1H), 5.39(s, 2H), 4.00(s, 3H), 3.57(s, 3H), 2.54(s, 3H). MS-ESI calcd. [M + H]+ 277, found 277.tert-Butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(5-methyl-1, 3, 4-oxadiazol-2-yl)propanoate (Racemate) To a solution of 750 mg (2.00 mmol) of tert-butyl[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate in 15 ml of THF were added, under argon at -70 C., 2.50 ml (2.50 mmol, 1.25 eq.) of 1N lithium bis(trimethylsilyl)amide in THF and the mixture was stirred for 30 min. Subsequently, 273 mul (2.66 mmol, 1.33 eq.) of General procedure: To a stirred suspension of10(30 mg, 0.07 mmol) and potassium carbonate (20 mg, 0.15 mmol) in DMF (500 muL) was added 2-bromoacetamide (15 mg, 0.11 mmol) and the mixture heated to 80 C for 1 h. The reaction mixture was concentrated to dryness and 4 MHCl/dioxane (1 mL) added. After concentrating to dryness, the residue was purified by prepHPLC(high pH) to afford the title compound(8 mg, 30%) as a white powder.33 mg of 2-(chloromethyl)-5-methyl-1, 3, 4-ox- adizaole (0.20 mmol; 1. leq) 4 mg of KI (0.02 mmoll 0.1 eq) and 80 mf of K2C03 (0.57 mmol; 2.5 eq) were introduced into a USP 16x100 tube. A solution of 80 mg of methyl 1 -[3-[2-hydroxy-5-(trifluoromethyl)phenyl] -phenyl]azetidine-3-carboxylate (preparation 124; 0.228 mmol; 1 eq) in 1 .5 mE of acetonitrile was added, and the reaction mixture was stirred on a l3ohdan block overnight at 60 C. The solvent was evaporated off under a nitrogen stream, then the residue was diluted with 1 mE of watet 0.5 mE of 1 M HC1 was added, then the aqueous phase was extracted with EtOAc. The organic phase was filtered on a hydrophobic membrane rinsed woth 1 mE of EtOAc, then dried under a nitrogen stream and on a Genevac for 15 h at 30 C. The residue was purified by EC-MS-prep (Euna C18, 50x250 mm 10 pm column (Phenomenex); Mobile phase H20/ acetonitrile) to give 24 mg of the title compound. Yld: 24%.

Molecular Weight:132.55
XLogP3:0.6
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:132.0090405
Monoisotopic Mass:132.0090405
Topological Polar Surface Area:38.9
Heavy Atom Count:8
Complexity:80.4
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes