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With N-chloro-succinimide In acetonitrile at 85℃; for 5 h;
4-Amino-3-chloro-5-fluorobenzonitrile A mixture of 4-amino-3-fluorobenzonitrile (1 equiv.) and N-chlorosuccinimide (1.5 equiv.) in acetonitrile (0.24 M) was stirred at 85° C. for 5 h. The solvent was removed by concentration and the residue was partitioned between ethyl acetate and 5percent NaOH. The organic phase was washed with 5percent NaOH and brine. Then the organic phase was dried over MgSO4 and dried in vacuum to afford 4-amino-3-chloro-5-fluorobenzonitrile (88percent) as a beige solid. 1H NMR (400 MHz, CDCl3) δ ppm: 7.41 (t, J=6 Hz, 1H), 7.24 (dd, J=1.8, 10.2 Hz, 1H), 4.66 (s, 2H).
With N-chloro-succinimide; In acetonitrile; at 85℃; for 5.0h;
4-Amino-3-chloro-5-fluorobenzonitrile A mixture of 4-amino-3-fluorobenzonitrile (1 equiv.) and N-chlorosuccinimide (1.5 equiv.) in acetonitrile (0.24 M) was stirred at 85 C. for 5 h. The solvent was removed by concentration and the residue was partitioned between ethyl acetate and 5% NaOH. The organic phase was washed with 5% NaOH and brine. Then the organic phase was dried over MgSO4 and dried in vacuum to afford 4-amino-3-chloro-5-fluorobenzonitrile (88%) as a beige solid. 1H NMR (400 MHz, CDCl3) delta ppm: 7.41 (t, J=6 Hz, 1H), 7.24 (dd, J=1.8, 10.2 Hz, 1H), 4.66 (s, 2H).
With N-chloro-succinimide; In acetonitrile; at 86℃; for 6.0h;
INTERMEDIATE 74-Amino-3-chloro-5-fluorobenzonitrile A solution of 4-amino-3-fluorobenzonitrile (25.13 g, 185 mmol) and NCS (24.65 g, 185 mmol) in acetonitrile (500 mL) was stirred at 86 C (reflux) for 5 h. LCMS showed -17% of starting material remained. Additional NCS (0.2 eq) was added and the reaction was stirred for 1 h. The reaction was partly concentrated and the residue was partitioned between 5% NaOH (100 mL) and EtOAc. The aqueous layer was back extracted with EtOAc. The organic extracts were dried over Na2S04 and concentrated to a pink solid. The NMR spectrum showed some of the succinimate side product still remained. The crude product was washed with H20 and air dried to give the desired product as a beige solid. This product was used in the next step without any futher purification. MS (m/z) 171.1 (M+H+).
With N-chloro-succinimide; In acetonitrile; at 86℃; for 6.0h;
4-Amino-3-chloro-5-fluorobenzonitrileA solution of 4-amino-3-fluorobenzonitrile (25.13 g, 185 mmol) and NCS (24.65 g, 185 mmol) in acetonitrile (500 mL) was stirred at 86 C (reflux) for 5 h. LCMS showed -17% of starting material remained. Additional NCS (0.2 eq) was added and the reaction was stirred for 1 h. The reaction was partly concentrated and the residue was partitioned between 5% NaOH (100 mL) and EtOAc. The aqueous layer was back extracted with EtOAc. The organic extracts were dried over Na2S04 and concentrated to a pink solid. The NMR spectrum showed some of the succinimate side product still remained. The crude product was washed with H20 and air dried to give the desired product as a beige solid. This product was used in the next step without any futher purification. MS (m/z) 171.1 (M+H+).
With N-chloro-succinimide; acetic acid; at 70℃; for 16.0h;
1.13. Synthesis of 4-amino-3-chloro-5-fluoro-benzonitrile (Int.21) A mixture of 4-amino-3-fluorobenzonitrile (184 mmol) and NCS (276 mmol) in AcOH (300 mL) was stirred at 70 C. for approximately 16 h. The mixture was concentrated. H2O was added to the residue and the solid product was filtered off and washed (sat. NaHCO3 and H2O). To eliminate H2O, THF was added and removed under reduced pressure to yield the desired product.
With N-chloro-succinimide; acetic acid; at 70℃; for 16.0h;
1.13. Synthesis of 4-amino-3-chloro-5-fluoro-benzonitrile (mt. 21) j00260j A mixture of 4-amino-3-fluorobenzonitrile (184 mmol) and NCS (276 mmol) in AcOH (300 mL) was stirred at 70C for approximately 16 h. The mixture was concentrated. H20 was added to the residue and the solid product was filtered off and washed (sat. NaHCO3 and H20). To eliminate H20, THF was added and removed under reduced pressure to yield the desired product.
With N-chloro-succinimide; acetic acid; at 70℃; for 0.16h;
A mixture of 4-amino-3-fluorobenzonitrile (184 mmol) and NCS (276 mmol) in AcOH (300 mE) was stirred at 70 C. for approximately 16 h. The mixture was concentrated. H20 was added to the residue and the solid product was filtered oil and washed (sat. NaHCO3 and H20). To eliminate H20, THF was added and removed under reduced pressure to yield the desired product.
With N-chloro-succinimide; In acetic acid; at 70℃; for 16.0h;
3.123. Compound 111: (lR,2R)-N-[6-(2-chloro-4-cyano-6-fluoro-N-methyl-anilino)-l-methyl- 3.123.1. Step i): 4-amino-3-chloro-5-fluoro-benzonitrile A mixture of 4-amino-3-fluorobenzonitrile (184 mmol) and NCS (276 mmol) in AcOH (300 mL) is stirred at 70C for approximately 16 h. The mixture is concentrated. H20 is added to the residue and the solid product is filtered off and washed (sat. NaHCC>3 and H20). To eliminate H20, THF is added and removed under reduced pressure to yield the desired product (Int. 21). 3.123.2. Step ii): 4-[[6-[bis[(4-methoxyphenyl)methyl]amino]-4-(methylamino)-5-nitro-2- pyridyl]amino]-3-chloro-5-fluoro-benzonitrtte
With sodium perborate tetrahydrate; acetic acid; In water; acetic acid; at 20 - 80℃; for 73.0h;
[0146] Sodium perborate tetrahydrate (131 g, 851 mmol) in acetic acid (200 mL) was heated to 60 C. A solution of<strong>[1147558-43-7]4-amino-3-chloro-5-fluorobenzonitrile</strong> (29.0 g, 170 mmol) in acetic acid (500 mL) was added dropwise, and the resultingreaction was stirred at 60C for 18 h. LCMS analysis indicated -50 % conversion. Additional sodium perborate tetrahydrate(14.4 g, 93.6 mmol) was added, and the reaction was stirred at 70C for 2 h followed by another addition of sodiumperborate tetrahydrate (70.0 g, 455 mmol). The reaction was stirred at 80 C for 5 h and then at rt for 2 d. The reactionwas poured into ice water, and the product was extracted into EtOAc. The combined organics were washed with waterand brine. Finally, the organics were dried over MgSO4, filtered, and concentrated to half volume. Addition of waterresulted in precipitation of the desired product which was collected in a frit, washed with water, and dried in vacuo toprovide an orange solid (27.5 g, 81 % crude yield). 1H NMR (400 MHz, CDCl3) delta 7.68 (s, 1H), 7.55 (d, 1 H).
With sodium perborate; acetic acid; at 20 - 80℃; for 71.0h;
3-Chloro-5-fluoro-4-nitrobenzonitrile Sodium perborate tetrahydrate (131 g, 851 mmol) in acetic acid (200 mL) was heated to 60 C. A solution of <strong>[1147558-43-7]4-amino-3-chloro-5-fluorobenzonitrile</strong> (29.02 g, 170 mmol) in acetic acid (500 ml.) was added dropwise and the reaction was stirred at 60 C for 16 h. The LCMS the indicated the reaction showed -50% conversion. Additional sodium perborate tetrahydrate (14.4 g) was added and the reaction stirred at 70 C for 2 h. Then additional sodium perborate tetrahydrate (70 g) was added and the reaction was stirred at 80 C for 5 h, followed by RT for 2 days. The reaction was then poured into ice water and extracted with EtOAc (3x). The combined organic extracts were washed with H20 (2x), brine, dried over MgS04 and concentrated. When most of the acetic acid was evaporated, water was added to the residue. The orange precipitate was collected by filtration, washed with H20 and air dried to give the crude product as an orange solid. NMR showed the product contaminated with -10% of starting material. This product was used without any further purification.
With sodium perborate tetrahydrate; acetic acid; at 20 - 80℃; for 71.0h;
3-Chloro-5-fluoro-4-nitrobenzonitrileSodium perborate tetrahydrate (131 g, 851 mmol) in acetic acid (200 mL) was heated to 60 C. A solution of <strong>[1147558-43-7]4-amino-3-chloro-5-fluorobenzonitrile</strong> (29.02 g, 170 mmol) in acetic acid (500 mL) was added dropwise and the reaction was stirred at 60 C for 16 h. The LCMS the indicated the reaction showed -50% conversion. Additional sodium perborate tetrahydrate (14.4 g) was added and the reaction stirred at 70 C for 2 h. Then additional sodium perborate tetrahydrate (70 g) was added and the reaction was stirred at 80 C for 5 h, followed by RT for 2 days. The reaction was then poured into ice water and extracted with EtOAc (3x). The combined organic extracts were washed with H20 (2x), brine, dried over MgS04 and concentrated. When most of the acetic acid was evaporated, water was added to the residue. The orange precipitate was collected by filtration, washed with H20 and air dried to give the crude product as an orange solid. NMR showed the product contaminated with -10% of starting material. This product was used without any further purification. 4-Chloro-1-r(3S,5S)-1-oxaspiror2.5loct-5-ylmethyll-1 H-benzimidazole-6-carbonitrile
3-chloro-5-fluoro-4-isothiocyanatobenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
With N-ethyl-N,N-diisopropylamine; at 0 - 20℃;
3-Chloro-5-fluoro-4-isothiocyanatobenzonitrile To a mixture of <strong>[1147558-43-7]4-amino-3-chloro-5-fluorobenzonitrile</strong> (1 equiv.) and DIEA (3.5 equiv.) in DCM (1 M) was added thiophosgene (3.5 equiv.) at 0 C. The reaction was stirred at room temperature overnight. The solvent was removed and the residue was purified by preparative TLC to give 3-chloro-5-fluoro-4-isothiocyanatobenzonitrile (34%) as a yellow solid. 1H NMR (400 MHz, CDCl3) delta ppm: 7.55 (t, J=1.6 Hz, 1H), 7.40 (dd, J=1.7, 8.5 Hz, 1H).
4-chloro-1-((-7-methyl-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile trifluoroacetic acid salt[ No CAS ]
6-chloro-N2,N2-bis(4-methoxybenzyl)-N4-methyl-3-nitropyridine-2,4-diamine[ No CAS ]
4-[[6-[bis[(4-methoxyphenyl)methyl]amino]-4-(methylamino)-5-nitro-2-pyridyl]amino]-3-chloro-5-fluorobenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl acetamide; at 120℃; for 16.0h;
3.123.2. Step ii): 4-[[6-[bis[(4-methoxyphenyl)methyl]amino]-4-(methylamino)-5-nitro-2- pyridyl]amino]-3-chloro-5-fluoro-benzonitrtte A mixture of 6-chloro-N2,N2-bis[(4-methoxyphenyl)methyl]-N4-methyl-3-nitro-pyridine-2,4- diamine (3.39 mmol), <strong>[1147558-43-7]4-amino-3-chloro-5-fluoro-benzonitrile</strong> (6.78 mmol) and CS2CO3 (13.6 mmol) in DMA (15 mL) is stirred for 16 h at 120 C. A solution of saturated NH4C1 is added to the mixture. The solid is filtered out and further washed with water. The solid is taken up in EtOAc and the organic mixture is washed (H20 and brine), dried (Na2S04) and concentrated. The residue is purified by flash column chromatography (S1O2, 100:0 to 50:50 petroleum ether/EtOAc) to afford the desired product.
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