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

A stirred solution of chloromethyl oxadiazole S56 (0.230 g, 1.94 mmol, 1.0 equiv) in triethyl phosphite (678 mg, 4.08 mmol, 2.1 equiv) was heated to 160 C. After 2 h, the triethyl phosphite was removed under a steady flow of nitrogen gas, and the reaction mixture was allowed to cool to 25 C. The obtained residue was purified by flash column chromatography (silica gel, 40- > 90% ethyl acetate in hexanes) to afford pure phosphonate 64 (375 mg, 1.70 mmol, 89% yield) as a colorless oil. 64: =0.25 (silica gel, ethyl acetate); FT-IR (neat) vmax 3476, 3075, 2985, 2934, 1646, 1551, 1479, 1445, 1395, 1370, 1343, 1255, 1163, 1139, 1107, 1051, 1021, 972, 959, 888, 831, 807, 762, 727 cm'1; NMR (600 MHz, CDCI3) 5 = 8.70 (s, 1 H), 4.21-4.15 (m, 4 H), 3.41 (d, 7= 21.6 Hz, 2 H), 1.34 (t, 7=7.2Hz, 6 H) ppm; 13C NMR (151 MHz, CDCI3) delta= 165.2, 163.3 (d, 7=9.2 Hz), 63.0 (d, 7=6.6 Hz), 24.9 (d, 7= 140.3 Hz), 16.5 (d, 7=6.0 Hz) ppm; HRMS (ESI) calcd for C7Hi3N204PNa+ [M+Na]+ 243.0505, found 243.0510.Ethyl 4- (4-chloro-2-fluorophenyl) -5, 6, 7, 8-tetrahydro-1, 7-naphthyridine-2-carboxylate (40 mg, 0.119 mmol) was placed under nitrogen in anhydrous DMF (0.5 ml) . Hunig's Base was added (0.04 ml, 31 mg, 0.239 mmol) , followed by 3- (chloromethyl) -1, 2, 4-oxadiazole (18 mg, 0.149 mmol) in anhydrous DMF (0.5 ml) . The reaction mixture was allowed to stir at room temperature. After 18 h the mixture was concentrated under reduced pressure. The resultant residue was dissolved in 7 N NH3in methanol (2.0ml) . The mixture was stirred 17 h at room temperature, then for 1 hour at 50 . The mixture was allowed to cool, then concentrated under reduced pressure. The resultant residue was dissolved in DMSO (1.5 ml) and purified by reverse phase preparative HPLC eluting with 8 to 40 MeCN in water (both with 0.1 TFA) over 10 min at 25 ml/min to provide the title compound. LC-MS: calculated for C18H15ClFN5O2387.09 observed m/e: 388.09 (M+H)+To a stirring solution of 3-(chloromethyl)-1 , 2, 4-oxadiazole (361 mg, 3.05 mmol) in DMF (13.8 mL) was added 8-chloro-1 , 7-naphthyridin-3-ol (400A) (500 mg, 2.77 mmol), tetrabutylammonium iodide (102 mg, 0.27 mmol) and potassium carbonate (765 mg, 5.54 mmol). The suspension was heated at 70 C for 45 min and then cooled to RT. The mixture was diluted with EtOAc (75 mL) and water (150 mL). The layers were separated and the aqueous layer was extracted with EtOAc (75 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 20-80% EtOAc/heptane to give twp products: the 1 st eluent, 2-((8-chloro- 1 , 7-naphthyridin-3-yl)oxy)acetonitrile (409) as a white solid (325 mg, 53%). LC/MS (ESI+) m/z = 220.1 (M+H)+. 1H NMR (400 MHz, chloroform-d) delta 8.89 (d, J=2.93 Hz, 1 H), 8.40 (d, J=5.48 Hz, 1 H), 7.61 (d, J=5.48 Hz, 1 H), 7.52 (d, J=2.93 Hz, 1 H), 5.00 (s, 2H). The 2nd eluent, 3-(((8-chloro-1 , 7-naphthyridin-3-yl)oxy)methyl)-1 , 2, 4-oxadiazole (410) as a white solid (149 mg, 20%). LC/MS (ESI+) m/z = 263.0 (M+H)+. 1H NMR (400 MHz, chloroform-d) delta 8.92 (d, J=2.93 Hz, 1 H), 8.84 (s, 1 H), 8.34 (d, J=5.67 Hz, 1 H), 7.53-7.59 (m, 2H), 5.47 (s, 2H).To a mixture of (S)-4-(2-fluorophenyl)-5 , 5 -bis(4-fluorophenyl)oxazo lidin-2-one (0.035 g, 0.09 mmol) (Example lOB) and 3-(chloromethyl)-l, 2, 4-oxadiazole (0.015g, 0.12 mmol)in THF under argon was added sodium hydride (0.008g, 60% dispersion in mineral oil, 0.19 nn-no 1) and the reaction stirred for 24h. After which time the mixture was neutralizedwith Amberlite 1R120 resin, filtered and concentrated. Purification by recrystallization from 20% EtOAc/n-Heptane afforded the titled product as white crystals. MS: (MH)408.1.[00124] To a solution of Boc-piperazine (571 mg, 3.07 mmol) and 3-(chloromethyl)- 1 , 2, 4-oxadiazole (400 mg, 3.37 mmol) in CH2CI2 (30 mL) was added triethylamine (1.70 mL, 12.3 mmol). The reaction was stirred for 22 h at 50 C before concentrated in vacuo to give a crude oily white solid. Purification was accomplished by flash chromatography on silica gel (4 x 12) eluting with MeOH/CH2CI2 (5%) to yield the title compound (555 mg, 67%) as a white solid. 1H-NMR (500 MHz, CDCI3) 1 .43 (s, 9H, C(CH3)3), 2.52 (app t, J = 4.9 Hz, 4H, CHz), 3.45 (app t, J = 4.9 Hz, 4H, CH2), 3.78 (s, 2H, CH2C-), 8.71 (s, 1 H, CHar); LC - MS (ESI, m/z): Rt = 1.67 min - 213 (M - 'Bu)+, 169 (M - Boc)+.3-(Chloromethyl)- 1, 2, 4-0 xadiazole (1.46 g) was dissolved in DMSO (40 mL) at RT under argon, treated with sodium cyanide (755 mg ) and the reaction mixture was stirred at RT for 4.5 h. The reaction mixture was then partitioned between H20 and EtOAc, the organic layer was extracted with EtOAc, the combined organic layers were dried over Na2S04 and then evaporated in vacuo to give the desired compound as a yellow liquid (0.949 g), which was used without further purification in the next reaction step. MS (EI): m/z = 109 [M]+.

Molecular Weight:118.52
XLogP3:0.6
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:117.9933904
Monoisotopic Mass:117.9933904
Topological Polar Surface Area:38.9
Heavy Atom Count:7
Complexity:60.9
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes