3-[4-(BROMOMETHYL)PHENYL]-5-METHYL-1,2,4-OXADIAZOLE

(5RS)-5-(Pyrrolidin-1-ylcarbonyl)-5, 6, 7, 8-tetrahydro[1, 2, 4]triazolo[4, 3-a]pyridin-3(2H)-one (racemate) (60.0 mg, 254 mumol) and caesium carbonate (124 mg, 381 mumol) were suspended in 3.0 ml of acetonitrile, then 5-[4-(bromomethyl)phenyl]-3-methyl-1, 2, 4-oxadiazole (70.7 mg, 279 mumol) was added and the mixture was stirred at room temperature over a weekend. For workup, the precipitate present was filtered off with suction and the filtrate was concentrated. Drying under reduced pressure was followed by purification by chromatography (instrument: Waters Prep LC/MS System, column: Phenomenex Kinetex C18 5 mum 100×30 mm; eluent A: water, eluent B: acetonitrile, flow rate: 65 ml/min plus 5 ml of 2% formic acid in water, room temperature, wavelength 200-400 nm, at-column injection (complete injection); gradient profile: 0 to 2 min 10% eluent B, 2 to 2.2 min to 20% eluent B, 2.2 to 7 min to 60% eluent B, 7 to 7.5 min to 92% eluent B, 7.5 to 9 min at 92% B). The product fraction was lyophilized. This gave 57.6 mg (54% of theory) of the title compound. (2302) LC-MS (Method 3): Rt=1.18 min; MS (ESIpos): m/z=409 [M+H]+ (2303) 1H-NMR (400 MHz, DMSO-d6): b [ppm]=1.62-1.85 (m, 4H), 1.88-2.12 (m, 4H), 2.48-2.72 (m, 2H, partially covered by solvent signal), 2.86 (s, 3H), 3.22-3.41 (m, 2H, partially overlapped by water signal), 3.47 (dt, 1H), 3.63 (dt, 1H), 4.76 (dd, 1H), 4.84-4.95 (m, 2H), 7.38-7.43 (m, 2H), 7.93-7.98 (m, 2H).Norfioxacin (3.1; 100 mg, 0.31 mmol, 1 eq)was added to a 1:1 mix of acetonitrile and distilled water ( mL total). After stirring for 5 minutes, potassium carbonate (130 mg, 0.94 mmol, 3 eq) was added and the mixture stirred for a further 5 minutes. Once fully dissolved, 3- (4-(bromomethyl)phenyl)-5-methyl-1, 2, 4-oxadiazole (mg, 0.30 mmol, 0.95 eq) was added slowly over the course of 1 hour and the mixture subsequently stirred for 7 days. Upon completion, the product was extracted with dichloromethane (2x20 mL) using a 1M solution of citric acid to neutralise the aqueous phase. Combined organic fractions were washed with distilled water (20 mL) and dried over MgSO4, filtered and concentrated in vacuo to give the crude product. Purification was achievedusing an SCX-2 catch and release cartridge (see Solid Phase Extraction method) to afford 3.36 as an off white solid. 1H NMR (400 MHz, CDC13) 6 15.13 (br. s., 1H), 8.63 (s, 1H), 8.02 (d, J = 8.31 Hz, 2H), 7.98 (d, J = 13.09 Hz, 1H), 7.48 (d, J = 8.06 Hz, 2H), 6.82 (d, J = 6.80 Hz, 1H), 4.31 (q, J = 7.05 Hz, 2H), 3.65 (s, 2H), 3.32 - 3.38 (m, 4H), 2.67 - 2.73 (m, 4H), 2.66 (s, 3H), i.6 (t, J = 7.18 Hz, 3H); 13C NMR (ioo MHz, CDC13) 6 176.9, 176.6, 168.2, 167.2, 152.3, 147.1, 146.2, 146.1, 141.1, 137.1, 129.5 (2C), 127.4 (2C), 125.9, 120.4, 120.3, 112.7, 112.5, 108.2, 103.8, 62.5, 52.7 (2C), 49.9, 49.9, 49.8, 14.4, 12.4; LC-MS Retention time 2.88minutes, Found 492.0 [M+H] calculated for C26H26FN504 492.52 [M+H]Ciprofloxacin (2.1; 100 mg, 0.30 mmol, 1 eq)was added to a 1:1 mix of acetonitrile and distilled water (s mL total). After stirring for s minutes, potassium carbonate (125 mg, 0.91 mmol, 3 eq) was added and the mixture stirred for a further minutes. Once fully dissolved, 3- (4-(bromomethyl)phenyl)-5-methyl-1, 2, 4-oxadiazole ( mg, 0.29 mmol, 0.95 eq) was added slowly over the course of 1 hour and the mixture subsequently stirred for 96 hours. Upon completion, the product was extracted with dichloromethane (2x20 mL) using a 1M solution of citric acid to neutralise the aqueous phase. Combined organic fractions were washed with distilled water (20 mL) and driedover MgSO4, filtered and concentrated in vacuo to give the crude product. Purification was achieved using an SCX-2 catch and release cartridge (see Solid Phase Extraction method) to afford (113.21 mg, 78.4 % yield) 2.40 as an off white solid. 1H NMR (400 MHz, CDC13) 6 15.01 (br. s., 1H), 8.73 (s, 1H), 8.01 - 8.06 (m, J = 8.31 Hz, 2H), 7.97 (d, J = 13.09 Hz, 1H), 7.46 - 7.51 (m, J = 8.06 Hz, 2H), 7.35 (d, J = 6.80 Hz, 1H), 3.66 (s, 2H), 3.54 (br. s., 1H), 3.37 (m, 4H), 2.71 (m, 4H), 2.67 (s, 3H), 1.38 (d, J =5.04 Hz, 2H), 1.19 (br. 5., 2H); 13C NMR (ioo MHz, CDC13) 6 177.1, 176.6, 168.2, 167.1, 147.4, 145.9, 141.2, 139.1, 129.5 (2C), 127.4 (2C), 125.9, 119.7, 112.5, 112.2, 108.1, 104.8, 62.6, 52.8, 49.9, 49.8, 35.3, 12.5, 8.2; LC-MS Retention time 2.87 minutes, Found504.0 [M+H] calculated for C27H26FN504 504.53 [M+H]Triethyl 2-(4-(5-methyl-1, 2, 4-oxadiazol-3-yl)phenyl)ethane-1, 1, 1-tricarboxylate 1o Prepared from A flask containing tetrahydrofuran (2.0 mL) was charged with sodium amide (152 mg, 3.69 mmol; Aldrich) and chilled to 0 0C. (4-Fluorophenyl)hydrazine hydrochloride (400 mg, 2.46 mmol; Aldrich) was added in portions. After 5 minutes, the solid had completely dissolved and the ice bath was removed. Stirring was continued for 1 hour, then the solution was chilled again in an ice bath and 3-(4-(bromomethyl)phenyl)-5-methyl-l, 2, 4-oxadiazole (623 mg, 2.46 mmol; Alfa Aesar) was added dropwise. After 30 minutes, the ice bath was removed and the reaction was heated to 50 0C overnight. The mixture was diluted with water (5 mL) and extracted with dichloromethane (2x10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: LC/MS (DCI/NEta3) m/z 282 (M+H-NH3)+.alpha-(4- Chlorophenylsulfonylamino)-3, 5-difluorobenzeneacetamide (300 mg, 0.83 mmol) was dissolved in DMF (5 mL). To this mixture was added 3-(4- (bromomethyl)phenyl)-5-methyl-l, 2, 4-oxadiazole (340 mg, 1.08 mmol), and CS2CO3 (810 mg, 2.5 mmol). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was then poured onto ethyl acetate (30 mL). The organic mixture was washed with saturated Na2Ctheta3 (10 mL) twice, then with brine (10 mL) twice. The organic solution was dried over MgSO4 and filtered; the filtrate was concentrated in vacuo. The crude residue was purified by medium pressure liquid chromatography (MPLC) using the Biotage Horizon 2.0 system (EtOAc:hexanes:: l:4 to 4: 1, total solvent volume = 2L) to give the title product as a white solid (117 mg, 26% yield): MS (ES+): 333 (M+ + H).After customary working up, the compound 2-isopropyl-3-[7-(5-methyl[1, 2, 4]oxadiazol-3-yl)naphth-2-ylmethyl]-5-[3-(5-methyl[1, 2, 4]oxadiazol-3-yl)benzyl]-3, 5-dihydroimidazo[4, 5-c]pyridin-4-one (BC1), m.p. 108-109, EI 571 is obtained Analogously, by reaction of 'BB' with 3-(7-bromomethylnaphthalen-2-yl)-5-methyl[1, 2, 4]oxadiazole, Analogously to Example 1, the compound 2-isopropyl-3-[3-(5-methyl[1, 2, 4]oxadiazol-3-yl)benzyl]-5H-imidazo[4, 5-c]pyridin-4-one (CA) is obtained by reaction of 'AB'with 3-(3-bromomethylphenyl)-5-methyl[1, 2, 4]oxadiazole. By reaction of 'CA' with 3-(3-bromomethylphenyl)-5-methyl[1, 2, 4]oxadiazole, 3-(7-bromomethylnaphthalen-2-yl)-5-methyl[1, 2, 4]oxadiazole, Example 17; l-Methyl'2-{(2R)-2-methyl-4-[4-(5-methyl-[l, 2, 4]oxadiazol-3-yl)-benzyl]-piperazin- 1-yl} IH- [4, 4']bipyrimidinyl-6-one; To a solution of l-methyl-2-((2R)-2-methyl-piperazin- 1-yl)- IH- [4, 4']bipyrimidinyl-6-one (0.15 g, 0.52 mmol) and potassium carbonate (0.22 g, 1.59 mmol) in jV^Af-dimethylformamide (1.5 ml) was added 3-[4-(bromomethyl)phenyl]- 5-methyl-l, 2, 4:oxadiazole (0.14 g, 0.55 mmol) at room temperature and the mixture was stirred for 4 hours. The mixture was partitioned between water and dichlorome thane, and the organic layer was washed with water, brine, and dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) to afford l-methyl-2-{(2R)- 2-methyl-4-[4-(5-methyl-[l, 2, 4]oxadiazol-3-yl)-benzyl] -piperazin- 1-yl}- IH- [4, 4'1 bipyrimidinyl-6-one (0.15 g, 63 %).

Molecular Weight:253.09
XLogP3:2.9
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:251.98983
Monoisotopic Mass:251.98983
Topological Polar Surface Area:38.9
Heavy Atom Count:14
Complexity:183
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes