* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With triphenylphosphine In toluene at 110℃; for 4 h;
Triphenylphosphine (1.1 mmol) was dissolved in dry toluene (3 mL) and stirred at 110°C under argon atmosphere; then, 6-bromobenzo[c][1,2,5]oxadiazole 1-oxide (1 mmol) in toluene (0.5 mL) was added dropwise over 1 hour and the resulting mixture was stirred for 3 hours [4]. After completion, the solvent was evaporated in vacuo, and the crude was purified through flash column chromatography (cyclohexane – diethyl ether 98:2), to afford the desired product as a pale pink solid. Yield: 60percent. TLC (cyclohexane – diethyl ether 98:2): Rf = 0.5. Mp: 74°C. 1H-NMR (300 MHz, DMSO) 8.49 (s, 1H, H4), 8.04 (d, J = 9.4 Hz, 1H, H7), 7.69 (dd, J = 9.4, 1.6 Hz, 1H, H6).
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 754 - 763
[2] Organic Process Research and Development, 2003, vol. 7, # 3, p. 436 - 445
[3] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 2, p. 233 - 235
2
[ 36387-84-5 ]
[ 51376-06-8 ]
Yield
Reaction Conditions
Operation in experiment
71%
With triethyl phosphite In ethanol at 60℃; for 1 h; Inert atmosphere
To a stirred solution of 5-bromobenzo[c][l,2,5]oxadiazole 1-oxide (6.0 g, 28.436 mmol) in ethanol (60 mL) was added triethyl phosphite (6.2 mL, 34.123 mmol) at RT under an inert atmosphere. The reaction mixture was then heated at 60 0C for 1 h., cooled to RT, diluted with hexane (100 mL) and stirred for 10 min. The precipitated solid was filtered off and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5- , bromobenzo[c][l,2,5] oxadiazole (4.0 g, 71percent) as a light yellow solid.
N-[((5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3.5-difluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl] acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; at 100℃; for 17h;
Cesium carbonate (0.23 g), 2,2'-bis(diphenylphosphino)-1,1'-binapthyl (0.06 g), 5- bromo-2,1,3-benzoxadiazol (0.12 g) and Tris -(dibenzylideneacetone) dipalladium(O) (0.1 EPO <DP n="55"/>g) were added to a solution of N-[(5S)-3-(3,5-difluoro-4-piperazin-1-ylphenyl)-2-oxo- l,3-oxazolidin-5-yl]methyl}acetamide (0.21 g) (which can be prepared according to Example 32(i) in U.S. Patent No. 5,547,950 at page 25) in dry dimethyl formamide (10 mL) and the reaction mixture was heated at 100 C for 17 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by column chromatography using 2 % methanol in dichloromethane as eluent to yield the title compound (0.025 g).Melting point: 207-213 C; EMS (m/z): 388;1HNMR(CDCl3): delta 7.91 (m, 2H), 7.62 (m, 2H), 7.52 (t, 1H), 7.35 (dd, 1H), 6.10 (t, 1H), 4.84 (m, 1H), 4.12 (t, 1H), 3.87 (t, 1H), 3.71 (m,2H), 2.02 (s, 3H).
N-[((5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3-fluorophenyl}-2-oxo-1,3-oxazolidin-5-yl)methyl]acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; at 100℃; for 17h;
Cesium carbonate (0.46 g), <strong>[51376-06-8]5-bromo-2,1,3-benzoxadiazole</strong> (0.23 g), 2,2'- bis(diphenylphosphino)-1,1'-binapthyl (0.074 g) and tris-(dibenzylideneacetone) dipalladium(O) (0.054 g) were added to a solution of N-[(5S)-3-(3-fluoro-4-piperazin-1- ylphenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (0.4 g) (which can be prepared according to Example l(k) in WO 93/23384, at page 14) in dry dimethyl formamide (15 mL) and the reaction mixture was heated at 100 C for 17 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by column chromatography using 2 % methanol in dichloromethane and sonicated in ether to yield the title compound (0.12 g).Melting point: 201-222 C; EIMS (m/z): 455;1HNMR(CDCl3): delta 7.71 (d, 1H), 7.48 (dd, 1H), 7.33 (dd, 1H), 7.12 (dd, 1H), 6.98 (t, 1H), 6.79 (s, 1H), 5.99 (t, 1H), 4.76 (m, 1H), 4.02 (t, 1H), 3.85-3.55 (m, 3H), 3.47 (m, 4H), 3.24 (m, 4H), 2.03 (s, 3H).
N-({(5S)-3-[4-(2,1,3-benzoxadiazol-5-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 100℃; for 3h;
<strong>[51376-06-8]5-bromo-2,1,3-benzoxadiazole</strong> (0.17 g) (which can be prepared according to Org. Proc. Res. Dev., (2003), 7, 436-445 at page 437), triethylamine (0.11 g) and dichlorobistriphenyl-phosphine palladium (II) (0.12 g) were added to a solution of N- ({(5S)-3-[3-fluoro-4-(trimethylstannyl)phenyl]-2-oxo-1,3-oxazolidin-5- yl}methyl)acetamide (0.18 g) (which can be prepared according to Example 8 of WO 01/94342, page 52) in dry dimethyl formamide (15 mL) and the reaction mixture was heated at 100 C for about 3 hours, cooled and diluted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography using 2 % methanol in dichloromethane as eluent to yield the title compound (0.14 g). Melting point: 156-165 C; EMS (m/z): 388 (M+H); 1HNMR(CDCB): delta 7.91 (m, 2H), 7.62 (m, 2H), 7.52 (t, 1H), 7.35 (dd, 1H), 6.10 (t, 1H), 4.84 (m, 1H), 4.12 (t, 1H), 3.87 (t, 1H), 3.71 (m,2H), 2.02 (s, 3H).
N-({(5S)-3-[4-(2,1,3-benzoxadiazol-5-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 100℃; for 3h;
Triethylamine (0.12 g), <strong>[51376-06-8]5-bromo-2,1,3-benzoxadiazole</strong> (0.19 g) and dichlorobistriphenylphosphine palladium(II) (0.13 g) were added to a solution of N-({(5S)- 3 - [3 , 5 -difluoro-4-(trimethylstannyl)phenyl] -2-oxo- 1 ,3 -oxazolidin-5 -yl } methyl)acetamide (0.21 g) (which can be prepared according to Example 8 of WO 01/94342, at page 52) in dry dimethyl formamide (15 mL) and the reaction mixture was heated at 100 C for about 3 hours. The reaction mixture was filtered and diluted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated. The crude EPO <DP n="44"/>product was purified by column chromatography using 2 % methanol in dichloromethane as eluent to yield the title compound (0.035 g).Melting point: 165-168 C; EMS (m/z): 388;1HNMR(CDC13): delta 7.92 (m, 2H), 7.48 (dd, 1H), 7.32 (dd, 2H), 5.98 (t, 1H), 4.85 (m, 1H), 4.09 (t, 1H), 3.84 (m, 1H), 3.72 (m, 2H), 2.03 (s, 3H).
(5R)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3-fluorophenyl}-5-(2H-1,2,3-triazoI-1-ylmethyl)-1,3-oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; at 100℃; for 17h;
<strong>[51376-06-8]5-bromo-2,1,3-benzoxadiazole</strong> (0.4 g), cesium carbonate (0.79 g), 2,2'- bis(diphenylphosphino)-1,1 '-binapthyl (0.1 g) and tris-(dibenzylideneacetone) dipalladium(O) (0.74 g were added) to (5R)-3-(3-fluoro-4-piperazin-1-ylphenyl)-5-(2H- l,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (0.7 g) (obtained from Step b) in dry dimethylformamide (15 mL) and the reaction mixture was heated at 100 C for about 17 hours. The reaction mixture was filtered, the solvent was evaporated and the crude product thus obtained was purified by column chromatography using 2 % methanol in dichloromethane to yield the title product (0.2g). Melting point: 215-220 C; EIMS (m/z): 465.21;1HNMR(DMSO): delta 7.91-7.83 (m,3H), 7.73 (d, 1H), 7.43 (dd, 1H), 7.13 (d, 2H), 6.89 (s, 1H), 5.18 (m, 1H), 4.86 (d, 2H), 4.22 (t, 1H), 3.91-3.86 (m, 1H), 3.48 (m, 4H), 3.14 (m, 4H).
(5R)-3-(4-[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; at 100℃; for 17h;
<strong>[51376-06-8]5-bromo-2,1,3-benzoxadiazole</strong> (0.61 g), cesium carbonate (1.2 g), 2,2'- bis(diphenylphosphino)-1,1' -binapthyl (0.51 g) and Tris -(dibenzylideneacetone) dipalladium(O) (0.11 g) were added to a solution (5R)-3-[3-fluoro-4-(piperidin-4- yloxy)phenyl]-5-(lH-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (1 g) (obtained from Step b) in dry dimethylformamide (10 mL) and the reaction mixture was heated at 100 C for about 17 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by column chromatography using 1 % methanol in dichloromethane to yield the title product (0.15g).Melting point: 148-150C; EIMS (m/z): 480.02;1HNMR(DMSO): delta 7.85 (d, 3H), 7.68 (d, 1H), 7.46 (dd, 1H), 7.28 (t, 1H), 7.15 (d, 1H), 6.85 (s, 1H), 5.2 (m, 1H), 4.86-4.85 (d, 2HO, 4.6 (m, 1HO, 4.22 (t, 1H), 3.9 (m, 1H), 3.72- 3.68 (m, 2H), 3.47-3.46 (d, 1H), 2.04 (m, 2H), 1.76 (m, 2H).
(5S)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3-fluorophenyl}-5-[(isoxazol-3-ylamino)methyl]-1,3-oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; at 100℃; for 17h;
5-bromo-2,1,3-benzoxadiazol (0.75 g), cesium carbonate (1.47 g), 2,2'- bis(diphenylphosphino)-1,1' -binapthyl (0.18 g) and Tris -(dibenzylideneacetone) dipalladium(O) (0.13 g) were added to a solution of (5S)-3-(3-fluoro-4-piperazin-1- ylphenyl)-5-[(isoxazol-3-ylamino)methyl]-1 ,3-oxazolidin-2-one (1.36 g) (obtained from Step b) in dry dimethylformamide(10 mL) and the reaction mixture was heated at 100 C for about 17 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by column chromatography using 1 % methanol in dichloromethane to yield the title product (0.1 g). Melting point: 213-215 C; EMS (m/z): 480.26, M+Na 502.22; EPO <DP n="49"/>1HNMR(DMSO): delta 8.38 (s, 1H), 7.88 (d, 1H), 7.72 (d, 1H), 7.53 (dd, 1H), 7.15 (m, 2H), 6.89 (s, 1H), 6.54 (t, 1H), 6.0 (s, 1H), 4.86 (m, 1H), 4.13 (t, 1H), 3.79 (t, 1H), 3.53 (m, 4H), 3.15 (m, 4H).
(5S)-3-(4-[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-5-[(isoxazol-3-ylamino)methyl]1-1,3-oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; at 100℃; for 17h;
5-bromo-2,1,3-benzoxadiazol (2.74 g) (which can be prepared according to Org. Proc. Res. Dev., (2003), 7, 436-445), cesium carbonate (5.38 g), 2,2'- bis(diphenylphosphino)-1,1'-binapthyl (0.68 g) and tris-(dibenzylideneacetone) dipalladium(O) (0.5 g) were added to a solution of (5S)-3-[3-fluoro-4-(piperidin-4- yloxy)phenyl]-5-[(isoxazol-3-ylamino)methyl]-1,3-oxazolidin-2-one (5 g) (obtained from Step b) in dry dimethylformamide (15 mL) and the reaction mixture was heated at 100 C for about 17 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by column chromatography using 1 % methanol in dichloromethane to yield the title product (0.4g). Melting point: 134-140 C; EIMS (m/z): 495.25;1HNMR(DMSO): delta 8.41 (s, 1H), 7.88 (d, 1H), (d, 1H), 7.6 (dd, 1H), 7.32 (t, 1H), 7.25 (d, 1H), 6.88 (s, 1H), 6.56 (t, 1H), 6.03 (s, 1H), 4.8 (m, 1H), 4.63-4.62 (m, 1H), 4.17 (t, 1H), 3.81 (m, 4H), 3.49-3.43 (m, 3H), 2.07 (m, 2H), 1.8 (m, 2H).
(5S)-3-[3-fluoro-4-(piperidin-4-yloxy)phenyl]-5-[(isoxazol-3-yloxy)methyl]-1,3-oxazolidin-2-one[ No CAS ]
(5R)-3-(4-[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-5-[(isoxazol-3-yloxy)methyl]-1,3-oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; at 100℃; for 17h;
<strong>[51376-06-8]5-bromo-2,1,3-benzoxadiazole</strong> (0.71 g), cesium carbonate (1.4 g), 2,2'- bis(diphenylphosphino)-1,r-binapthyl (0.17 g) and Tris-(dibenzylideneacetone) dipalladium(O) (0.13g) were added to a solution of (5S)-3-[3-fluoro-4-(piperidin-4- yloxy)phenyl]-5-[(isoxazol-3-ylamino)methyl]-1,3-oxazolidin-2-one (1.3 g) (obtained from Step b) in dry dimethylformamide (15 mL) and the reaction mixture was heated at 100 C for about 17 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by column chromatography using 1 % methanol in dichloromethane to yield the title product (0.07g).Melting point: 75-100 C; EIMS (m/z): 534.21; 1HNMR(DMSO): delta 8.16 (s, 1H), 7.66 (d, 1H), 7.48 (dd, 1H), 7.3 (m, 2H), 7.17 (d, 1H), 7.08-7.05 (t, 1H), 6.75 (s, 1H), 4.99 (m, 1H), 4.53 (m, 3H), 4.14-4.11 (t, 1H), 3.95 (t, 1H), 3.61 (m, 2H), 3.3 (m, 2H), 2.04 (m, 4H).
(5R)-3-{4-[4-(2,1,3-benzoxadiazol-5-yl)piperazin-1-yl]-3-fluorophenyl}-5-[(isoxazol-3-yloxy)methyl]-1,3-oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In N,N-dimethyl-formamide; at 100℃; for 17h;
<strong>[51376-06-8]5-bromo-2,1,3-benzoxadiazole</strong> (0.52 g), cesium carbonate (1.01 g), 2,2'- bis(diphenylphosphino)-1,1' -binapthyl (0.13 g) and tris-(dibenzylideneacetone) dipalladium(O) (0.09 g) were added to a solution of (5R)-3-(3-fluoro-4-piperazin-1- ylphenyl)-5-[(isoxazol-3-yloxy)methyl]-1,3-oxazolidin-2-one (0.91 g) (obtained from Step b) in dry dimethylformamide (15 mL) and heated at 100 C for about 17 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by column chromatography using 80 % ethyl acetate in hexane to yield the title product (0.03g).Melting point: 125-143 C; EIMS (m/z): 481.25; 1HNMR(DMSO): delta 8.69 (s, 1H), 7.88 (d, 1H), 7.73 (d, 1H), 7.53 (dd, 1H), 7.24 (d, 1H), 7.15 (t, 1H), 6.89 (s, 1H), 6.39 (s, 1H), 4.99 (m, 1H), 4.47 (m, 2H), 4.18 (t, 1H), 3.91 (t, 1H), 3.53 (m, 4H), 3.15 (m, 4H).
N-[(5S)-3-(4-[1-(2,1,3-benzoxadiazol-5-yl)piperidin-4-yl]oxy}-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 48h;
<strong>[51376-06-8]5-bromo-2,1,3-benzoxadiazole</strong> (0.14 g) and diisopropyl ethylamine (1.16 mL) were added to a solution of tert-butyl 4-(4-{(5S)-5-[(acetyl amino)methyl]-2-oxo-1,3- EPO <DP n="54"/>oxazolidin-3-yl}-2-fluorophenoxy)piperidine-1-carboxylate (0.3 g) (which can be prepared according to Example 7 in Biorg. Med. Chem. Lett., 11 (2001), 1829-1832 at page 1830) in acetonitrile and the reaction mixture was heated at 80 C for about 48 hours. The reaction mixture was filtered and the solvent was evaporated. The crude product thus obtained was purified by preparative thin layer chromatography using 5 % methanol in dichloromethane to yield the title product (0.03 g).Melting point: 96-100 C; EIMS (m/z): 470.13;1HNMR(CDCl3): delta 7.6 (dd, 1H), 7.47 (dd, 1H), 7.30 (d, 1H), 7.06 (m, 2H), 6.73 (dd, 1H), 5.94 (6s, 1H), 4.76 (m, 1H), 4.49 (m, 1H), 4.03 (t, 1H), 3.76-3.44 (m, 6H, 3.28 (m, 1H), 2.03 (m, 7H).
(2-benzo[1,2,5]oxadiazol-5-yl-phenyl)-dimethyl-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
523 mg (1.65 eq. ) bis (PINACOLATO) diboran, 552 mg (4.5 eq. ) potassium acetate and 51 mg (0.01 eq. ) PDCL (DPPF)-CH2CI2 are added to a solution of 373 mg 5-bromo-benzo [1,2, 5] oxa- DIAZOLE in 8 mL DMF and heated to 80C under continuous stirring for 6 hours. 662 mg (5 eq. ) sodium carbonate in 3.3 mL water are added together with 500 mg (1 eq. ) 2-bromo- N, N-dimethylaniline and 51 mg (0.01 eq. ) PDCL (dppf)-CH2CI2 to the reaction mixture, which is stirred for another 18 hours at 80C, cooled to room temperature and extracted with ethyl acetate and water. The combined organic phases are washed with brine, dried over magnesium sulfate and evaporated. The residue is column chromatographed (hexane, then HEXANE/ETHYL acetate 8: 1) to yield the desired product as an orange resin. MS (ES+): 240 (M+1).
(4-benzo[1,2,5]oxadiazol-5-yl-phenyl)-dimethyl-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
500 mg (2.5 MMOL) 5-bromo-benzo [1,2, 5] oxadiazole and 313 mg (0.1 eq. ) tetrakis- (triphenylphosphine) palladium are stirred for 30 minutes at room temperature in 10 mL 1,2- dimethoxyethane. 533 mg (2 eq. ) sodium carbonate are dissolved in 1.8 mL water and added to the reaction mixture, followed by 663 mg (1.6 eq. ) 4- (dimethylamino) phenylboronic acid. After stirring at REFLUX FOR 18H, the reaction mixture is cooled to room temperature and extracted with ethyl acetate and water. The organic phases are combined, dried with magnesium sulfate, filtered and evaporated. The residue is column chromatographed (hexane, then HEXANE/ETHYL acetate 8: 1 then 5: 1) to yield the desired product as a yellow solid. MS (ES+): 240 (M+1).
In N,N-dimethyl-formamide; at 140℃; for 24h;Inert atmosphere;
To a stirred solution of 5-bromobenzo[c][l, 2, and 5] oxadiazole (2.0 g, 10.050 mmol) in DMF (50 mL) was added CuCN (1.79 g, 230.10 mmol) at RT under an inert atmosphere. The reaction mixture was then heated at 140 0C for 24 h., cooled to RT, diluted with water (10 mL) and stirred for 10 min. The precipitated solid was filtered off and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford benzo[c][l,2,5]oxadiazole-5- carbonitrile (0.7 g, 48 %) as a yellow solid.
With triethyl phosphite; In ethanol; at 60℃; for 1h;Inert atmosphere;
To a stirred solution of 5-bromobenzo[c][l,2,5]oxadiazole 1-oxide (6.0 g, 28.436 mmol) in ethanol (60 mL) was added triethyl phosphite (6.2 mL, 34.123 mmol) at RT under an inert atmosphere. The reaction mixture was then heated at 60 0C for 1 h., cooled to RT, diluted with hexane (100 mL) and stirred for 10 min. The precipitated solid was filtered off and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5- , bromobenzo[c][l,2,5] oxadiazole (4.0 g, 71%) as a light yellow solid.
5-(2,1,3-benzoxadiazol-5-yl)-N-cyclopentyl-2-methylpyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11%
Example 49: 5-(2,1,3-benzoxadiazol-5-yl)-/V-cyclopentyl-2-methylpyrimidin-4-amine:; In a flask under argon were placed 200 mg (1.00 mmles, 1.0 eq.) of 5-bromo-2,1,3- benzoxadiazole, 326 mg (1.10 mmoles, 1.10 eq.) of bis(pinacolato)diboron, 986 mg (3.32 mmoles, 3.30 eq.) of AcOK, and 8 mg (0.01 mmoles, 0.01 eq.) of PdCI2(dppf). 3.5 mL of anhydrous DMF were added and the mixture was stirred at 800C for 6h. It was cooled to RT and 170 mg (0.66 mmoles, 0.66 eq.) of 5-bromo-Lambda/-cyclopentyl-2-methylpyrimidin-4-amine, 8 mg (0.01 mmoles, 0.01 eq.) of PdCI2(dppf) were added followed by a solution of 352 mg (3.32 mmoles, 3.30 eq.) of Na2CO3 in 1.41 mL of water. The mixture was heated at 800C for 15h. The experiment was allowed to cool to RT. The solution was partitioned between 35 mL of water and 15 mL of AcOEt. The aqueous phase was extracted two more times with 15 mL of AcOEt. The combined organic layers were washed once with 15 mL of brine, dried over Na2SO4, filtered and evaporated to dryness. The crude compound was purified by flash chromatography on silica gel. The crude compound was then recrystallized in 1 mL of hot MeOH. The solution was cooled to RT, evaporated to the half and left overnight in the fridge. EPO <DP n="79"/>The solid was filtered off, washed with 2 ml. of Et2O and dried under high vacuum to give 34 mg of a yellow solid. Yield : 11 % M.P. : 165-167C LC-MS : Tr = 3.61 min. (100 %) (ES-MS: m/z 296.2 (M+H)) [Column : Nucleosil C-18HD, 4x70 mm, 3mum, gradient CH3CN/H2O/TFA 0.05% : 20-100% CH3CN (6 min.), 100% CH3CN (1.5 min.), flow : 1 mL/min].1H-NMR (CDCI3, 400 MHz) delta : 1.34-1.45 (m, 2H) ; 1.62-1.74 (m, 4H) ; 2.08-2.17 (m, 2H) ; 2.59 (s, 3H) ; 4.52 (quint, J = 7.0 Hz, 1H) ; 4.80 (d, J = 7.0 Hz, 1H) ; 7.42 (d, J = 9.5 Hz, 1H) ; 7.84 (s, 1H) ; 7.96 (d, J = 9.5 Hz, 1H) ; 8.04 (s, 1H).13C-NMR (CDCI3, 100 MHz) delta : 23.9 ; 26.1 ; 32.9 ; 52.2 ; 114.2 ; 115.5 ; 117.7 ; 132.9 ; 138.7 ; 148.4 ; 149.3 ; 153.9 ; 158.4 ; 168.1.
With lithium chloride;tetrakis(triphenylphosphine) palladium(0); In toluene; for 3h;Inert atmosphere; Reflux;
-Bromo-2,l,3-benzoxadiazole (10 g, 50.3 mmol) was dissolved in toluene (300 mL) and treated with lithium chloride (6.39 g, 151 mmol) , Pd(Ph3P)4 (2.90 g, 2.51 mmol), and allyltributylstannane (18.66 ml, 60.3 mmol). Degassed and refluxed the mixture under N2 for 3 hrs. The reaction mixture turned black. Poured the reaction mixture into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried, and evaporated to dryness. The residue was chromatographed through 12Og ISCO Redi-Sep column and eluted with 0-10% ethyl acetate / hexane to yield 5-(prop-2-en-l-yl)-2,l,3-benzoxadiazole
With tetrakis(triphenylphosphine) palladium(0); lithium chloride; In toluene; at 110℃; for 2h;Inert atmosphere;
Step A: 5-Allyl-2,l,3-benzoxadiazoleTo a 250 mL flask charged with 5-Bromo-2,l,3-benzoxadiazole (5.0 g, 25 mmol), Palladium Tetrakis (0.87 g, 0.75 mmol), and lithium chloride (2.1 g, 50 mmol) was added Allyl Tri-n- butyltin (10 g, 30 mmol) and toluene (100 mL). The mixture was attached to a reflux condenser, sealed and purged with nitrogen. The reaction was heated to 1 10 C for 2 hours. TLC showed good and complete reaction. The reaction was diluted with EtOAc, washed with brine, concentrated and purified by silica gel chromatography.
With tetrakis(triphenylphosphine) palladium(0); lithium chloride; In toluene; for 3h;Inert atmosphere; Reflux;
5-Bromo-2,1,3-benzoxadiazole (10 g, 50.3 mmol) was dissolved in toluene (300 ml) and added Lithium chloride (6.4 g, 150 mmol), Pd(Ph3P)4 (2.90 g, 2.50 mmol), and allyl tributyltin (19 ml, 60 mmol). The reaction mixture was degassed and refluxed under N2 for 3 hrs. It was cooled and poured into water then extracted with ethyl acetate. The organic layer was washed with brine 1x, dried and evaporated to dryness. The residue was chromatographed through 120g ISCO Redi-Sep columns and eluted with 0-10% ethyl acetate / hexane to yield 5-allyl-2,1,3-benzoxadiazole. 1H-NMR (500 MHz, DMSO): delta ppm 7.96 (d, J=9.1 Hz, 1H), 7.44(d, J= 9.1 Hz, 2H), 5.95-6.04 (m, 1H), 5.17 (d, J=14.7Hz, 1H), 5.15 (d, J=8.9Hz, 1H), 3.50 (d, J= 6.7Hz, 2H)
With triethylamine;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In ethanol; for 3h;Reflux;
5-Brorno-2,l,3-benzoxadiazole (5.5 g, 27.6 mmol)), potassium vinylfluoroborate (7.40 g, 55.3 mmol), and PdC12(dppi>;CH2C12Adduct (1.088 g, 1.332 mmol) were suspended in ethanol (75 ml) then added TEA (7.70 ml, 55.3 mmol). The reaction mixture was then degassed and heated to reflux for 3hrs. The reaction was diluted with ethyl acetate and washed with brine. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was purified through a 330g ISCO Redi-Sep silica gel plug and eluted with 20%ETOAc/hexane to yield 5- ethenyl-2 , 1 , 3 -benzoxadiazole.1H-NMR (600 MHz5 CDCl3): delta ppm 7.81(d, J=9.3 Hz, IH), 7.66 (s, IH), 7.63 (d, J-9.3 Hz, IHX 6.35 (d, J=10.9 Hz, 0.5H), 6.80 (d, J-10.9 Hz, 0.5H)s 5.94 (d. J-17.5 Hz, IH)5 5.55 (d, J= H Hz5 IH).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine; In ethanol; at 80℃; for 12h;
Step A: 5-ethenyl-2, 1 ,3-benzoxadiazole: 5-bromo-2, 1 ,3-benzoxadiazole (4.0 g, 20 mmol),potassium vinyltrifluoroborate (5.40 g, 40.2 mmol) and Pd(dppf)Clr (1.6 g, 2 mmol) in TEA (5.2mL) and EtOH (15 mL) were added to a flask containing a stir bar, and the flask was then heated at 80 C for 12h. The organic residue was dissolved in EtOAc (500 mL) and the solution was washed with brine, dried over sodium sulfate, filtered and concentrated. The resulting organic residue was subjected to purification over silica gel to give the title compound.
With copper(l) iodide; bis(triphenylphosphine)palladium(II) dichloride; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 12h;Inert atmosphere;
Step A: l-r4-(2,l,3-Benzoxadiazol-5-ylethvnyl)-4-hvdroxypiperidin-l-yl1-2-r4-(lH-tetrazol-l- vDphenyll ethanone 5-bromo-2, 1 ,3-benzoxadiazole (0.11 g, 0.55 mmol), 1 -(4-ethynyl-4-hydroxypiperidin- 1 -yl)-2- [4-(lH-tetrazol-l-yl)phenyl]ethanone (0.16 g, 0.50 mmol), copper (I) iodide (0.0048 g, 0.025 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.070g, 0.1 mmol) were combined in DMF (2 mL) and flushed with nitrogen. Triethylamine (0.14 mL, 1.0 mmol) was added, the vessel sealed and the mixture heated in an oil bath at 80 C for 12 h. The mixture was cooled, diluted with water and extracted with ethyl acetate (3x). The combined organic layers were washed successively with water (2x) and brine, then dried (Na2S04), filtered and concentrated. Purification by MPLC (eluent gradient 10->50% EtOAc:hex.) provided l-[4-(2,l,3- benzoxadiazol-5 -ylethynyl)-4-hydroxypiperidin- 1 -yl] -2- [4-( lH-tetrazol- 1 -yl)phenyl] ethanone . 1H NMR (500 MHz, CDC13, delta in ppm): 9.06 (s, 1H), 7.93 (s, 1H), 7.82 (d, J= 9.5 Hz, 1H), 7.70 (d, J= 8.5 Hz, 2H), 7.50 (d, J= 8.5 Hz, 2H), 7.36 (d, J= 9.0 Hz, 1H), 4.02 (m, 1H), 3.88 (s, 2H), 3.81 (m, 1H), 3.68 (m, 1H), 3.58 (m, 1H), 3.07 (br s, 1H), 2.06 (m, 2H), 1.90 (m, 2H). LC-MS (IE, m/z): 430 [M+l]+.
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 12h;Inert atmosphere; Sealed tube;
[0325] <strong>[51376-06-8]5-bromo-2,1,3-benzoxadiazole</strong> (0.11 g, 0.55 mmol), 1-(4-ethynyl-4-hydroxypiperidin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone (0.16 g, 0.50 mmol), copper (I) iodide (0.0048 g, 0.025 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.070g, 0.1 mmol) were combined in DMF (2 mL) and flushed with nitrogen. Triethylamine (0.14 mL, 1.0mmol) was added, the vessel sealed and the mixture heated in an oil bath at 80 C for 12 h. The mixture was cooled,diluted with water and extracted with ethyl acetate (3x). The combined organic layers were washed successively withwater (2x) and brine, then dried (Na2SO4),filtered and concentrated. Purification by MPLC (eluent gradient 10->50%EtOAc:hex.) provided 1-[4-(2,1,3-benzoxadiazol-5-ylethynyl)-4-hydroxypiperidin-1-yl]-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone.1H NMR (500 MHz, CDCl3, delta in ppm): 9.06 (s, 1H), 7.93 (s, 1H), 7.82 (d, J = 9.5 Hz, 1H), 7.70 (d, J = 8.5 Hz,2H), 7.50 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 9.0 Hz, 1H), 4.02 (m, 1H), 3.88 (s, 2H), 3.81 (m, 1H), 3.68 (m, 1H), 3.58 (m,1H), 3.07 (br s, 1H), 2.06 (m, 2H), 1.90 (m, 2H). LC-MS (IE, m/z): 430 [M+1]+.
N-2,1,3-benzoxadiazol-5-yl-6-(methylsulfonyl)-4-quinolinamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
14%
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 120℃; for 0.333333h;Inert atmosphere; Microwave irradiation;
6-(Methylsulfonyl)-4-quinolinamine (50 mg, 0.225 mmol), <strong>[51376-06-8]5-bromo-2,1,3-benzoxadiazole</strong>, Pd2dba3 (20.60 mg, 0.022 mmol), BINAP (14.01 mg, 0.022 mmol), and sodium tert-butoxide (43.2 mg, 0.450 mmol) were added to a vial which was purged with nitrogen. Toluene (2250 mul) was then added and the reactions were heated to 120 C for 20 min via microwave. It was then concentrated, redissolved in DMSO, filtered, and purified by RP HPLC to afford the title compound as a solid (11 mg, 14 %). 1H NMR (400 MHz, DMSO-d6) delta 9.26 (s, 1H), 8.82 (d, J = 5.1 Hz, 1H), 8.39 (d, J = 8.5 Hz, 1H), 8.23 (m, 2H), 7.95 (br. s, 1H), 7.72 (d, J = 9.5 Hz, 1H), 7.40 - 7.46 (m, 1H), 3.38 (s, 3H); MS (m/z) 341.1 (M+H+).
A solution of <strong>[51376-06-8]5-bromobenzo[c][1,2,5]oxadiazole</strong> (3 g , 15.0 mmol, Combiblocks ) in toluene (10 mL) was degassed for 30 min. 1 -Ethoxy vinyl tributyltin (6.01 mL, 16.5 mole, Frontier Scientific) and bis(triphenylphosphine)palladium(ll) dichloride (1.16 g, 1 .65 mmol) were added at rt and the resulting mixture was stirred at 90 C overnight. It was cooled to rt and filtered through celite. HCl aqueous solution (20 mL, 6N) was added and the mixture was stirred for 1 hour at rt. It was concentrated and neutralized with sat. NaHCO3 solution (25 mL). The product was extracted with DCM (100 mL), dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography to afford the title compound. Yield: 60% (1 .5 g, pale yellow solid). 1 H NMR (400 MHz, DMSO-d6): delta 8.90 (s, 1H), 8.14 (d, J = 9.6 Hz, 1H), 7.98-7.39 (m, 1H), 2.72 (s, 3H). LCMS: (Method B) 162.0 (M+H), Rt. 4.6 min, 98.01 % (Max).
[00779] Intermediate 85: 2,1 ,3-benzoxadiazol-5-amine[00780] In a dry, nitrogen purged 5-10 mL microwave tube were successivelly introduced 5-bromo-2,1 ,3-Benzoxadiazole (200mg, 1.01 mmol), Pd2(dba)3 (46mg, 0.OSmmol) and tri-tertbutylphosphonium tetrafluoroborate (58mg, 0.2Ommol) and toluene (1 mL). The tube was evacuated/backfilled with nitrogen and then sealed. Lithium bis(trimethylsilyl)amide (1.0 M in toluene, 2mL, 2mmol) was added and the reaction mixture was thermally heated at 50 C overnight. After cooling to room temperature, the reaction mixture was diluted with ether (2OmL) and thesilylamide was deprotected by adding 2-3 drops of 1 M HCI(aq). The mixture was transferred to a separatory funnel and washed with sat. aq. NaHCO3 (lOmL). The organic layer was dried over Na2504, filtered and concentrated in vacuo. The residue was purified via column chromatography using an eluent of 0-100% EtOAc in heptane. Three main fractions were collected containing the expected product and unprotected I partially deprotecetd silyl amide. The fractions were pooled,concentrated in vacuo and the residue dissolved in THF (1 mL). 1 M HCI(aq) (1 mL) was added and the mixture was stirred at room temperature for 1 hour. The mixture was made alkaline with 1 M NaOH(aq) and extracted with EtOAc (3 x 1 OmL). The combined organic layers were washed with brine (l0mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified via column chromatography using an eluent of 0-100% EtOAc in heptane to give 2,1 ,3-benzoxadiazol-5-amine (57mg, 0.42mmol, 42%) as a yellow-green solid.1H NMR (DMSO-d6, 400MHz) O/ppm: 7.76 (1H, dd, J= 9.5Hz, 0.6Hz), 7.14 (1H, dd, J= 9.5Hz,1.8Hz), 6.43 (2H, brs), 6.35 (1H, dd, J= 1.8Hz, 0.6Hz).MS Method 2: RT: 1.22 mi mlz 136.0 [M+H]
tert-butyl 4-[(E)-2-(2,1,3-benzoxadiazol-5-yl)ethenyl]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With palladium diacetate; triethylamine; In N,N-dimethyl-formamide; at 100℃; for 2h;Inert atmosphere;
[0077] In a 15 mL microwave tube was added <strong>[51376-06-8]5-bromo-2,1,3-benzoxadiazole</strong> (0.94 g, 4.7 mmol), tert-butyl 4-ethenylpiperidine-1-carboxylate (1.0 g, 4.7 mmol), triethylamine (0.66 ml, 4.7 mmol), palladium (II) acetate (0.11 mg, 0.47 mmol)and DMF (5 mL). The solution was degassed and filled with nitrogen (3x), then heated to 100 C for 2 hr. The reactionwas diluted with ethyl acetate, washed with water, filtered through a pad of diatomaceous earth and a plug of silica gel.The organic phase was dried over MgSO4, concentrated and purified by MPLC (eluted with gradient 0->30% EtOAc/Hexane)to provide tert-butyl 4-[(E)-2-(2,1,3-benzoxadiazol-5-yl)ethenyl]piperidine-1-carboxylate as a mixture with the Zolefin.LC-MS (IE, m/z): 352 [M+Na]+.
tert-butyl 2-(benzo[γ][1,2,5]oxadiazol-5-yl)-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 120℃; for 0.2h;Inert atmosphere; Sealed tube; Microwave irradiation;
A microwave vial containing tert-butyl 3-oxo-2,8-diazaspiro[4.5]decane-8- carboxylate (INTERMEDIATE 15) (200 mg, 0.786 mmol), 5-bromobenzo[Y][l,2,5]oxadiazole (156 mg, 0.786 mmol), Pd2(dba)3 (144 mg, 0.157 mmol), Xantphos (182 mg, 0.315 mmol) and cesium carbonate (384 mg, 1.18 mmol) in dioxane (3.9 mL) was sealed and evacuated and purged with nitrogen before heating in microwave to 120C for 12 min. The reaction was cooled, partitioned between EtOAc (150 mL) and water (40 mL). The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude material, which was purified via MPLC (30-80% EtOAc/hexanes) to afford tert-butyl 2-(benzo[y][l,2,5]oxadiazol-5-yl)-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate. LC-MS (372, m/z): 373 [M+l]+.
1-(2-((2S,4R)-4-fluoro-2-((2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)-1H-indazole-3-carboxamide[ No CAS ]
1-(2-((2S,4R)-2-((3-benzo[c][1,2,5]oxadiazol-5-yl)-2-fluorophenylcarbamoyl)-4-fluoropyrrolidin-1-yl)-2-oxoethyl)-1H-indazole-3-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 0.75h;Inert atmosphere; Microwave irradiation;
l-(2-((2S,4R)-4-Fluoro-2-((2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)carbamoyl)pyrrolidin-l-yl)-2-oxoethyl)-lH-indazole-3-carboxamide, 5- bromobenzo[c][l,2,5]oxadiazole, Pd(dppf)Cl2 and potassium carbonate were taken up in a pressure tube under argon. To this mixture, 8 mL of dioxane and 2 mL of water were added. The mixture was bubbled with argon for 5 min and the vial was stoppered and subjected to microwave irradiation at 100 C for 45 min. The volatiles were removed under reduced pressure and the residue was purified by ISCO (0-5 % MeOH in CH2CI2) to afford compound 68. 1HNMR (400 MHz, DMSO) (major rotamer) delta 2.10 - 2.20 (m, 1H), 2.57-2.63 (m, 1H), 3.89 - 4.04 (m, 1H), 4.24 (dd, J = 12.7, 21.8 Hz, 1H), 4.78 (t, J = 8.3 Hz, 1H), 5.47 (d, J= 17.2 Hz, 1H), 5.55 (d, J = 52.4 Hz, 1H), 5.67 (d, j = 17.2 Hz, 1H), 7.23-7.31 (m, 2H), 7.36 (s, 1H), 7.39 - 7.46 (m, 2H), 7.59 - 7.64 (m, 2H), 7.74 (d, J= 9.3 Hz, 1H), 7.98 (t, J= 7.8 Hz, 1H), 8.11 - 8.25 (m, 3H), 10.05 (s, 1H). 19F- MR (DMSO-de ) (major rotamer): delta -128.8, -175.9.
(5-(methoxycarbonyl)furan-2-yl)boronic acid[ No CAS ]
[ 51376-06-8 ]
methyl 5-(benzo[c][1,2,5]oxadiazol-5-yl)furan-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; at 60℃; for 1h;Inert atmosphere;
General procedure: Methyl 5-boronofuran-2-carboxylate (8, 1.3mmol), the appropriate bromo derivatives (10, or 12, or 13, 1.0mmol) and bis(triphenylphosphine)palladium (II) dichloride (5% mol) were dissolved in dry 1,4-dioxane (10mL), under nitrogen atmosphere. A 2M sodium carbonate solution (2mmol) was then added and the resulting mixture was stirred in a microwave synthesizer (Biotage Initiator Classic) for 1hat 60C. After completion, the solution was cooled to room temperature and then filtered on a celite pad. The filtrate was diluted with water and extracted with ethyl acetate (3×4mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.
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