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was raised to RT in 10 min. Then, a solution of 1-(benzotriazol-1yl)-2-(4-isobutylphenyl)propan-1-one (204 mg, 0.66 mmol) in dry DMSO (3.5 mL, 5 mL/mmol) was added dropwise to the reaction mixture. After 4 h of stirring at RT, the mixture was poured into water (15 mL, 4 5 mL/mmol), acidified with acetic acid 10% and extracted with ethyl acetate (3 15 mL). Organic layers were combined, washed with brine (3 40 mL), dried over MgSO4, filtered and concentrated under vacuum. After purification by flash chromatography (hexane/ethyl acetate 10:1), 122 mg (69%) of a yellow oil were obtained. Rf 0.15 (hexane/ethyl acetate 10:1); 1 H NMR (500 MHz, CDCl3) d 0.90 (d, 3 J ¼ 6.6 Hz, 6H), 1.48 (d, 3 J ¼ 6.9 Hz, 3H), 1.85 (m, 1H), 2.47 (d, 3 J ¼ 7.2 Hz, 2H), 3.80 (q, 3 J ¼ 6.9 Hz, 1H), 5.12 (d, 2 J ¼ 14.7 Hz, 1H), 5.20 (d, 2 J ¼ 14.7 Hz, 1H), 7.10 (d, 3 J ¼ 8.1 Hz, 2H), 7.16 (d, 3 J ¼ 8.1 Hz, 2H); 13 C NMR (125 MHz, CDCl3) d 17.2, 22.6, 30.4, 45.3, 51.8, 82.1, 127.9, 130.7, 135.2, 142.3, 196.6; FT-IR (ATR-SeZn, cm 1 ) n 2956 (s), 1735 (s), 1562 (s), 1382 (m), 1035 (w), 671 (w); MS (APCI) m/z: 248 [M H] ; HRMS calcd for C14H19NO3Na: 272.1263, found: 272.1259. 4.2.9. 1-(N-Hydroxyimino)-3-(4-isobutylphenyl)butan-2-one (7a) To a stirred solution of SnCl2.H2O (230 mg, 1.21 mmol), PhSH (370 mL, 3.59 mmol) and NEt3 (510 mL, 3.61 mmol) in acetonitrile (4 mL) was added a solution of 3-(4-isobutylphenyl)-1-nitrobutan- 2-one (200 mg, 0.80 mmol) in 1 mL of acetonitrile. After 1 h the solvent was removed under reduced pressure, water (10 mL) was added and the resulting solution was extracted with diethyl ether (3 10 mL). The combined organic layers were washed with NaHCO3 (sat.), brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane/ethyl acetate 10:1); 75 mg (40%) of yellow oil were obtained. Rf 0.22 (hexane/ethyl acetate 10:1); 1 H NMR (300 MHz, CDCl3) d 0.88 (d, 3 J ¼ 6.6 Hz, 6H), 1.43 (d, 3 J ¼ 7.1 Hz, 3H), 1.83 (m, 1H), 2.42 (d, 3 J ¼ 7.2 Hz, 2H), 4.55 (q, 3 J ¼ 7.1 Hz, 1H), 7.07 (d, 3 J ¼ 8.1 Hz, 2H), 7.14 (d, 3 J ¼ 8.1 Hz, 2H), 7.50 (s, 1H); 13 C NMR (75 MHz, CDCl3) d 18.0, 22.7, 30.4, 45.3, 47.0, 128.1, 129.8, 137.3, 140.9, 149.1, 198.8; FT-IR (ATR-SeZn, cm 1 ) n 3315 (m), 2952 (s), 1674 (s), 1604 (w), 1510 (m), 1456 (s), 1382 (w), 1267 (w), 1169 (m), 1069 (m), 1004 (s), 927 (w), 849 (m), 796 (w), 767 (w), 690 (m); MS (APCI) m/z: 234 [M þ H] þ , 216 [M OH] þ ,201[M OH CH3] þ ,161[M C2H2NO2] þ ; HRMS calcd for C14H19NO2Na: 256.1313, found: 256.1307. 4.2.10. 2-(4-Isobutyl-phenyl)-propionyl chloride (8a) To a suspension of ibuprofen sodium salt (1.47 g, 6.4 mmol) in dry diethyl ether (20 mL) was added dropwise oxalyl chloride (605 mL, 7.05 mmol) at 0 C under Ar atmosphere and the mixture was stirred for 4 h. The mixture was filtered, concentrated under vacuum, diluted with hexane, filtered again and evaporated under vacuum to obtain 1.32 g (92%) of colourless liquid. 1 H NMR (500 MHz, CDCl3) d 0.90 (d, 6H),1.59 (d, 3H),1.86 (m,1H), 2.47 (d, 2H), 4.09 (q, 1H), 7.15 (d, 2H), 7.20 (d, 2H); 13 C NMR (75 MHz, CDCl3) d 19.0, 22.7, 30.4, 45.3, 57.4, 127.9, 130.1, 134.8, 142.1, 176.0. 4.2.11. 3-(4-Isobutylphenyl)-1-bromo- and 1-chloro-butan-2-one (10a) and (11a) To a solution of 2-(4-isobutyl-phenyl)-propionyl chloride (1.32 g, 5.87 mmol) in diethyl ether (50 mL) at 0 C was added dropwise a diethyl ether solution of diazomethane (see Arndt, F. Organic Synthesis Coll.1943, 2,165) until acyl chloride was perfectly consumed (disappearance of the yellow colour of CH2N2 solution). After removing the solvent under vacuum, acetic acid (6 mL) was added. The solution was cooled to 0 C and aqueous HBr (47%, 1.3 mL) was added dropwise slowly. The mixture was allowed to warm to RT and was stirred for 1 h. Then the solution was poured into cold water (10 mL), neutralized with Na2CO3 to pH 7. The solution was extracted F. De Wael et al. / European Journal of Medicinal Chemistry 45 (2010) 3564e3574 3571 with ethyl acetate (3 30 mL), the combined organic layers were washed with water, brine then dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography (hexane/diethylether 97:3) to obtain 352 mg (25%) of 3-(4-isobutylphenyl)-1-bromobutan-2-one as a colourless oil and 243 mg (26%) of 3-(4-isobutylphenyl)-1-chlorobutan-2-one as a colourless oil (CAUTION: protect from light for storage). 10a: Rf 0.24 (hexane/diethylether 97:3); 1 H NMR (300 MHz, CDCl3) d 0.90 (d, 3 J ¼ 6.6 Hz, 6H), 1.43 (d, 3 J ¼ 6.9 Hz, 3H), 1.85 (m, 1H), 2.45 (d, 3 J ¼ 7.2 Hz, 2H), 3.78 (d, 2 J ¼ 12.7 Hz, 1H), 3.92 (d, 2 J ¼ 12.7 Hz, 1H), 4.10 (q, 3 J ¼ 6.9 Hz, 1H), 7.12 (s, 4H); 13 C NMR (75 MHz, CDCl3) d 17.8, 22.5, 30.3, 33.5, 45.1, 49.8, 127.7, 130.1, 136.8, 141.4, 202.0; FT-IR (ATR-SeZn, cm 1 ) n 2953 (s), 1732 (s), 1651 (w), 1510 (m), 1464 (m), 1454 (m), 1385 (m), 1282 (w), 1167 (m), 1018 (s), 848 (s), 796 (m); MS (CI/CH4) m/z: 285 [M ( 81 Br) þ H] þ , 283 [M ( 79 Br) þ H] þ , 161 [M C2H2OBr] þ ; MS (ESI) m/z: 590 [2 M ( 81 Br) þ Na] þ , 588 [M ( 81 Br) þ M( 79 Br) þ Na] þ , 586 [2 M( 79 Br) þ Na] þ , 307 [M ( 81 Br) þ Na] þ , 305 [M ( 79 Br) þ Na] þ ; HRMS calcd for C14H19ONaBr: 305.0517, found: 305.0517. 11a: Rf 0.19 (hexane/diethylether 97:3); 1 H NMR (300 MHz, CDCl3) d 0.90 (d, 3 J ¼ 6.6 Hz, 6H), 1.43 (d, 3 J ¼ 6.9 Hz, 3H), 1.85 (m, 1H), 2.45 (d, 3 J ¼ 7.2 Hz, 2H), 3.98 (q, 3 J ¼ 6.9 Hz, 1H), 4.02 (d, 2 J ¼ 15.4 Hz, 1H), 4.09 (d, 2 J ¼ 15.4 Hz, 1H), 7.12 (s, 4H); 13 C NMR (75 MHz, CDCl3) d 17.7, 22.5, 30.3, 45.1, 47.4, 49.9, 127.7, 130.1, 136.6, 141.4, 202.3; FT-IR (ATR-SeZn, cm 1 ) n 2955 (s), 1732 (s), 1510 (m), 1464 (m), 1454 (m), 1382 (m), 1333 (w), 1284 (w), 1166 (m), 1111 (m),1064 (m),1020 (m), 848 (s), 796 (s), 781 (m); MS (FAB) m/z:240 [M ( 37 Cl)] þ , 238 [M ( 35 Cl)] þ ,161[M C2H2OCl] þ ; HRMS calcd for C14H19ONaCl: 261.1022, found: 261.1020. 4.2.12. 3-(4-Isobutylphenyl)-1-nitrate-butan-2-one (12a) To a solution of 3-(4-isobutylphenyl)-1-bromobutan-2-one (268 mg, 0.95 mmol) in dry acetonitrile (5 mL) was added AgNO3 (340 mg, 2.0 mmol) at RT and the mixture was stirred for 40 h. The mixture was filtered on a flash silice pad and concentrated under vacuum to obtain 241 mg (96%) of yellow oil. 1 H NMR (300 MHz, CDCl3) d 0.89 (d, 3 J ¼ 6.6 Hz, 6H), 1.45 (d, 3 J ¼ 7.0 Hz, 3H), 1.85 (m, 1H), 2.46 (d, 3 J ¼ 7.2 Hz, 2H), 3.78 (q, 3 J ¼ 7.0 Hz, 1H), 4.82 (d, 2 J ¼ 17.5 Hz, 1H), 4.91 (d, 2 J ¼ 17.5 Hz, 1H), 7.13 (s, 4H); 13 C NMR (75 MHz, CDCl3) d 17.0, 22.5, 30.3, 45.1, 49.8, 73.0, 127.7, 130.1, 135.8, 141.7, 201.6; FT-IR (ATR-SeZn, cm 1 ) n 2955 (s), 1736 (s), 1645 (s), 1512 (m), 1454 (m), 1404 (m), 1365 (m), 1283 (s), 1130 (w), 1058 (w), 1008 (m), 970 (m), 941 (w), 847 (s), 800 (m), 752 (w); MS (CI/CH4) m/z: 265 [M] , 218 [M HNO2] , 161 [M C2H2OBr] þ ; MS (ESI) m/z: 288 [M þ Na] þ ; HRMS calcd for C14H19NO4Na: 288.1212, found: 288.1210. 4.2.13. 1-Bromo-3-phenylpropan-2-one (10c) To a solution of 2-phenylacetyl chloride (670 mL, 5.06 mmol) in diethyl ether (15 mL) at 0 C was added a diethyl ether solution of diazomethane until acyl chloride was perfectly consumed. After removing the solvent under vacuum, acetic acid (6 mL) was added. The solution was cooled to 0 C and aqueous HBr (47%, 1 mL) was added dropwise slowly. The mixture was allowed to warm to RT and was stirred for 1 h. Then the solution was poured into cold water (10 mL), neutralized with Na2CO3 to pH 7. The solution was extracted with ethyl acetate (3 30 mL), the combined organic layers were washed with water, brine then dried over MgSO4, filtered and concentrated under vacuum to obtain 818 mg of a colourless oil. As the NMR spectrum showed only two products, 1-bromo-3-phenylpropan-2-one as major product (w90%) and 1chloro-3-phenylpropan-2-one as minor product (
3572 NMR (75 MHz, CDCl3) d 33.4, 46.7, 127.4, 129.4, 128.9, 133.1, 199.3; FT-IR (NaCl, cm 1 ) n 3059 (m), 3030 (m), 2936 (s), 1725 (s), 1495 (m), 1391 (m), 1181 (m), 1045 (s), 739 (m); MS (CI/CH4) m/z:215[M ( 81 Br) þ H] þ , 213 [M ( 79 Br) þ H] þ . 11c: Yield: 8%; Rf 0.36 (hexane/diethylether 97:3); 1 H NMR (300 MHz, CDCl3) d 3.90 (s, 2H), 4.12 (s, 2H), 7.22e7.38 (m, 5H); 13 C NMR (75 MHz, CDCl3) d 45.1, 52.2, 127.4, 128.7, 129.9, 132.2, 194.1; MS (CI/CH4) m/z: 171 [M ( 37 Cl) þ H] þ , 169 [M ( 35 Cl) þ H] þ . 4.2.14. 2-Hydroxy-3-phenyl-2-propenal (5 0 c) A solution of 1-bromo-3-phenylpropan-2-one (810 mg, 3.8 mmol) in DCM (40 mL) was refluxed in the presence of pyridine (1.3 mL) under Ar atmosphere for 2 h. Concentration of the solution under vacuum afforded the pyridinium salt as a solid. The solid was dissolved in water (40 mL) and N,N-dimethyl-4-nitrosoaniline (600 mg, 4.00 mmol) was added at 0 Cfollowedby1Maqueous NaOH (4 mL). The resulting suspension was allowed to reach RT and stirred for 2 h with sonicating occasionally. The suspension was filtered and the solid was suspended into 10% aqueous H2SO4 (50 mL) at 0 C. The suspension was warmed to RT and stirred 2 h with sonicating occasionally. The suspension was extracted with diethyl ether (2 50 mL) and the combined organic layers were washed with water (2 ) and brine. The solutionwas dried with Na2SO4, filtered and concentrated under vacuum to obtain 347 mg (62%) of a brown solid. 1 H NMR (300 MHz, CDCl3) d 6.18 (s, 1H), 6.60 (s, 1H, OH), 7.40 (m, 3H), 7.85 (d, 3 J ¼ 7.8 Hz, 1H), 9.25 (s, 1H); 13 C NMR (75 MHz, CDCl3) d 122.9, 128.9, 129.5, 130.6, 133.7, 148.8, 188.4; MS (APCI, positive mode) m/z: 181, 167, 149 [M þ H] þ ,131[M OH] þ , 120 [M CO] þ ; MS (APCI, negative mode) m/z: 179, 147 [M H] , 117; MS (ESI) m/z: 181, 167, 149 [M þ H] þ . 4.2.15. 2-Phenylimidazo[1,2-a]pyrazin-3-(7H)-one (17a) 2-Aminopyrazine hydrochloride (14a) was prepared from commercial 2-aminopyrazine (solution in ether) and 2 M HCl (5 eq.). The precipitated salt was filtered off and washed with ether. A solution of 2-aminopyrazine hydrochloride (133 mg, 1.02 mmol) and phenylglyoxal (308 mg, 2.02 mmol) in ethanol (4 mL) was heated (at 80 C) in Microwave (Mw) oven at 150 W for 5 min, then at 75 W of 4 h. After concentration under vacuum, the residue was dissolved in methanol (0.5 mL) and the product was precipitated by addition of diethyl ether to furnish 165 mg of a dark red solid (66%). 1 H NMR (500 MHz, CD3OD) d 7.49 (m, 3H), 7.64 (d, 3 J ¼ 5.6 Hz,1H), 8.23 (d, 3 J ¼ 5.6 Hz,1H), 8.25 (d, 3 J ¼ 6.9 Hz, 2H), 8.79 (s,1H); 13 CNMR (125 MHz, CD3OD) d 116.1,119.4,128.2,129.9,130.0,130.6,130.9,132.0, 138.5, 146.7; FT-IR (ATR-SeZn, cm 1 ) n 3096 (s), 2923 (s), 1668 (m), 1573 (s),1497 (s),1448 (m),1367 (w),1288 (w),1230 (s),1124 (s),1088 (w), 1070 (w), 1000 (w), 906 (m), 775 (s), 696 (s); MS (ESI) m/z: 212 [M þ H] þ ;HRMScalcdforC12H9N3ONa: 234.0643, found: 234.0638; UVevis (MeOH, 10 4 M): lm (nm) 466, 287. 4.2.16. 2-Phenyl-6-p-hydroxyphenylimidazo[1,2-a]pyrazin-3(7H)one (17b) To a stirred solution of 2-amino-5-(p-hydroxyphenyl)-1,4-pyrazine (180 mg, 0.96 mmol) and phenylglyoxal (306 mg, 1.97 mmol) in ethanol (3 mL) was added concentrated HCl (36%) (310 mL) and the mixture was heated at reflux overnight. The reaction mixture was concentrated under vacuum. The product was precipitated by addition of diethyl ether to the residue dissolved in a minimum of methanol. After two precipitations, 225 mg (69%) of a dark red solid were obtained. 1 H NMR (500 MHz, DMSO-d6) d 6.89 (d, 3 J ¼ 8.6 Hz, 2H), 7.36 (t, 3 J ¼ 7.9 Hz, 1H), 7.47 (t, 3 J ¼ 7.9 Hz, 2H), 7.65 (d, 3 J ¼ 8.6 Hz, 2H), 7.99 (s, 1H), 8.38 (d, 3 J ¼ 7.9 Hz, 2H), 8.41 (s, 1H); 1 H NMR (300 MHz, CD3OD) d 6.94 (d, 3 J ¼ 8.4 Hz, 2H), 7.49e7.55 (m, 3H), 7.71 (d, 3 J ¼ 8.4 Hz, 2H), 8.12 (d, 3 J ¼ 7.2 Hz, 2H), 8.42 (s, 1H), 8.89 (s, 1H); 13 C F. De Wael et al. / European Journal of Medicinal Chemistry 45 (2010) 3564e3574 NMR (125 MHz, DMSO-d6) d 108.1, 115.8, 122.7, 126.1, 127.5, 127.6, 128.4, 128.5, 128.6, 129.2, 129.4, 132.5, 147.8, 158.5; 13 C NMR (75 MHz, CD3OD) d 111.9, 117.2, 123.7, 128.2, 128.8, 129.5, 129.9, 130.2, 131.2, 133.0, 137.2, 161.2 (two quaternary carbons not detected); FT-IR (ATR-SeZn, cm 1 ) n 3149 (m), 2964 (m), 1662 (m), 1608 (s), 1516 (s), 1448 (m), 1346 (w), 1218 (s), 1155 (s), 1016 (w), 920 (w), 837 (m), 769 (m), 690 (w); MS (ESI) m/z: 304[Mþ H] þ . 4.2.17. 2-Phenylimidazo[1,2-a]pyrazin-3(7H)-imine (18a) A solution of 2-aminopyrazine chlorohydrate (134 mg,1.02 mmol) and phenylglyoxal aldoxime (315 mg, 2.11 mmol) in ethanol (4 mL) was heated (at 80 C) in a Mw oven at 150 W for 5 min, then at 75 W overnight. The reaction mixture was concentrated under vacuum. The product was precipitated by adding diethyl ether to the residue dissolved in a minimum of methanol. After two precipitations, 159 mg (64%) of a dark red solid were obtained. M.p.: >225 C, decomposition; 1 H NMR (300 MHz, CD3OD) d 7.51 (m, 3H), 7.65 (d, 3 J ¼ 5.6 Hz, 1H), 7.93 (d, 3 J ¼ 7.8 Hz, 2H), 8.30 (d, 3 J ¼ 5.6 Hz, 1H), 8.79 (s, 1H); 13 CNMR(75MHz,CD3OD) d 116.1, 119.2, 128.6, 130.2, 130.8, 131.8, 132.6, 133.4, 137.4, 141.9; FT-IR (ATR-SeZn, cm 1 ) n 3120 (s), 1633 (s), 1556 (m), 1467 (s), 1404 (s), 1296 (w), 1261 (w), 1217 (m),1130 (w),1060 (s),1022 (w), 905 (w), 775 (m), 696 (m); MS (ESI) m/z: 211[Mþ H] þ ;HRMScalcdforC12H11N4: 211.0984, found: 211.0983; UVevis (MeOH, 10 4 M): lm (nm) 429, 269. 4.2.18. 2-Phenyl-6-p-hydroxyphenylimidazo[1,2-a]pyrazin-3(7H)imine (18b) To a solution of 2-amino-5-(p-hydroxyphenyl)-1,4-pyrazine (181 mg, 0.97 mmol) and phenylglyoxal aldoxime (301 mg, 2.02 mmol) in ethanol (4 mL) was added concentrated HCl (36%, 310 mL) and the mixture was heated (at 80 C) in a Mw oven at 150 W for 5 min, then at 100 W for 4 h. The reaction mixture was concentrated under vacuum. The product was precipitated by addition of diethyl ether to the residue dissolved in a minimum of methanol. After two precipitations, 98 mg (30%) of a dark red solid were obtained. M.p.: >250 C, decomposition; 1 H NMR (300 MHz, CD3OD) d 6.98 (d, 3 J ¼ 8.7 Hz, 2H), 7.49 (t, 3 J ¼ 7.5 Hz,1H), 7.55 (t, 3 J ¼ 7.5 Hz, 2H), 7.68 (d, 3 J ¼ 8.7 Hz, 2H), 7.93 (d, 3 J ¼ 7.5 Hz, 2H), 8.50 (s, 1H), 8.79 (s, 1H); 13 C NMR (125 MHz, CD3OD) d 111.6, 117.3, 123.2, 128.6, 129.5, 130.3, 130.9, 131.8, 132.0, 132.7, 134.5, 136.6, 140.2, 161.2; FT-IR (ATR-SeZn, cm 1 ) n 2927 (s), 2854 (m), 1652 (m), 1612 (m), 1452 (m), 1252 (m), 1111 (s), 1056 (m), 837 (s), 779 (m), 698 (m); MS (ESI, positive mode) m/z:303[Mþ H] þ ; MS (ESI, negative mode) m/z:301[M H] ;HRMS calcd for C18H15N4O: 303.1246, found: 303.1244. 4.3. Evaluations 4.3.1. Inhibition of lipid peroxidation A micellar solution of linoleic acid (4 mM) containing Tween 20 as surfactant in phosphate buffer (50 mM, pH 7.4) and EDTA (0.1 mM) is incubated at 37 C with 2 mM AAPH (2,2 0 -azo-bis (2-amidinopropane)-dihydrochloride) as the free-radical generator. The production of conjugated dienes by the peroxidation of linoleate is monitored continuously at 234 nm using a wavelength tuneable microplate spectrophotometer reader (SpectraMAX 190, Molecular Devices). Antioxidant efficiency of the tested compound was evaluated by the lag phase duration until onset of peroxidation. Tested compounds were initially dissolved in ethanol (10 2 M) then in phosphate buffer (50 mM, pH 7.4); they were assayed at final concentrations of 1.25, 2.5, 5, 10 and 20 mM. 4.3.2. Anti-inflammatory assay The human intestinal Caco-2 cells (ATCC, Rockville, MD), used between passages 30 and 50 were routinely grown in DMEM containing 4.5 g/l glucose, 25 mM Hepes, 10% (v/v) fetal calf
Page 1 and 2: Original article Chemistry around i
Page 3 and 4: 3566 R 1 OH R2 O 1a: R1 =Me,R2 = iB
Page 5 and 6: 3568 an antioxidant agent should le
Page 7: 3570 4.2. Organic chemistry 4.2.1.
Page 11: 3574 [38] P. Shah, V. Jogani, T. Ba

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