cyanomethyl(trimethyl)phosphanium;iodide

Conditions: temp:97.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of anthracen-9-yl-methanol (6.58 g, 31.6 mmol) and (cyanomethyl)trimethylphosphonium iodide (19.19 g, 78.96 mmol) in propionitrile (77 mL) was added diisopropylethylamine (DIPEA, 49.4 mL, 94.74 mmol) and the mixture was stirred at 97° C. for 20 hours. Water (3.82 mL) was added, nitrogen was bubbled though the mixture, and the mixture was stirred for 20 hours. Water (480 mL) and concentrated HCl (19 mL) were added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated. The resulting solid was purified by silica gel column chromatography (hexane:CHCl3=1:1) to give 3-anthracen-9-yl-propionitrile as brown crystals (6.93 g, 95% yield). 1H NMR (CDCl3) δ 8.43 (1H, s), 8.19 (2H, d), 8.05 (2H, d), 7.60 (2H, dd), 7.51 (2H, dd), 4.02 (2H, t), 2.79 (2H, t). nitrogen was bubbled though the mixture the mixture was stirred for 20 hours Water (480 mL) and concentrated HCl (19 mL) were added the mixture was extracted with EtOAc The organic layer was washed with brine dried over MgSO4 concentrated The resulting solid was purified by silica gel column chromatography (hexane:CHCl3=1:1)

Conditions: temp:97.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of anthracen-9-yl-methanol (6.58 g, 31.6 mmol) and (cyanomethyl)trimethylphosphonium iodide (19.19 g, 78.96 mmol) in propionitrile (77 mL) was added diisopropylethylamine (DIPEA, 49.4 mL, 94.74 mmol) and the mixture was stirred at 97° C. for 20 hours. Water (3.82 mL) was added, nitrogen was bubbled though the mixture, and the mixture was stirred for 20 hours. Water (480 mL) and concentrated HCl (19 mL) were added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated. The resulting solid was purified by silica gel column chromatography (hexane:CHCl3=1:1) to give 3-anthracen-9-yl-propionitrile as brown crystals (6.93 g, 95% yield). 1H NMR (CDCl3) δ 8.43 (1H, s), 8.19 (2H, d), 8.05 (2H, d), 7.60 (2H, dd), 7.51 (2H, dd), 4.02 (2H, t), 2.79 (2H, t). nitrogen was bubbled though the mixture the mixture was stirred for 20 hours Water (480 mL) and concentrated HCl (19 mL) were added the mixture was extracted with EtOAc The organic layer was washed with brine dried over MgSO4 concentrated The resulting solid was purified by silica gel column chromatography (hexane:CHCl3=1:1)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Cyanomethyl)trimethylphosphonium iodide (45 mg) was added to a mixture of 40 (Burger, A.; Sawhney, S. N. J. Med. Chem. 1968, 11, 270-273) (33 mg, 0.2 mmol), 6-mercaptopurine riboside (42 mg, 0.2 mmol) and DIPEA (0.04 ml) in 0.43 ml of propionitrile. The mixture was heated at 90° C. and few drops of DMF were added to obtain a clear solution. Stirring was continued overnight at 90° C. The mixture was cooled to room temperature, water was added and slowly a pale brown precipitate was formed. The solid was collected and dried under vacuum. 1H NMR (CD3OD): δ9.20, 8.74 (2×s, 2H), 8.59 (s, 1), 8.18 (s, 1H), 7.98 (d, 1H, J=8.78 Hz), 7.67 (d, 1H, J=8.77 Hz), 6.07 (d, 1H, J=5.11 Hz), 4.84 (s, 2H), 4.72 (m, 1H), 4.35 (m, 1H), 4.17 (m, 2H), 3.83 (m, 1H);13C-NMR (CDCl3/d6-DMSO): 6161.5, 157.1, 153.5, 152.8, 149.5, 144.6, 137.4, 135.2, 129.0, 124.0, 123.7, 90.6, 87.6, 75.7, 72.2, 63.0, 33.2, 19.4; Mp=decomp. 140° C.; HRMS calc. for C18H18N5O4S2 m/Z=432.5100 (M+H), found 432.0787. to obtain a clear solution The mixture was cooled to room temperature slowly a pale brown precipitate was formed The solid was collected dried under vacuum 140° C.

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Cyanomethyl)trimethylphosphonium iodide (45 mg) was added to a mixture of 40 (Burger, A.; Sawhney, S. N. J. Med. Chem. 1968, 11, 270-273) (33 mg, 0.2 mmol), 6-mercaptopurine riboside (42 mg, 0.2 mmol) and DIPEA (0.04 ml) in 0.43 ml of propionitrile. The mixture was heated at 90° C. and few drops of DMF were added to obtain a clear solution. Stirring was continued overnight at 90° C. The mixture was cooled to room temperature, water was added and slowly a pale brown precipitate was formed. The solid was collected and dried under vacuum. 1H NMR (CD3OD): δ9.20, 8.74 (2×s, 2H), 8.59 (s, 1), 8.18 (s, 1H), 7.98 (d, 1H, J=8.78 Hz), 7.67 (d, 1H, J=8.77 Hz), 6.07 (d, 1H, J=5.11 Hz), 4.84 (s, 2H), 4.72 (m, 1H), 4.35 (m, 1H), 4.17 (m, 2H), 3.83 (m, 1H);13C-NMR (CDCl3/d6-DMSO): 6161.5, 157.1, 153.5, 152.8, 149.5, 144.6, 137.4, 135.2, 129.0, 124.0, 123.7, 90.6, 87.6, 75.7, 72.2, 63.0, 33.2, 19.4; Mp=decomp. 140° C.; HRMS calc. for C18H18N5O4S2 m/Z=432.5100 (M+H), found 432.0787. to obtain a clear solution The mixture was cooled to room temperature slowly a pale brown precipitate was formed The solid was collected dried under vacuum 140° C.

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Cyanomethyl)trimethyl-phosphonium iodide 36 (299 mg, 1.23 mmol) was added to a mixture of alcohol 35 (200 mg, 1.35 mmol), 6-mercaptopurine riboside (284 mg, 1.00 mmol), and DIPEA (0.25 mL) in propionitrile (3 mL). The mixture was heated at 90° C. and some drops of DMF were added to obtain a clear solution. The mixture was stirred overnight at 90° C., cooled to room temperature and water was added. Upon standing at room temperature, 37 was formed as a pale brown precipitate collected by filtration and dried in vacuo (65% yield). 1H NMR (d6-DMSO): δ 8.83, 8.72 (2×s, 2H), 8.21 (s, 1H), 7.70 (s, 1H), 7.54 (d, 1H, J=8.04 Hz), 7.31 (d, 1H, J=8.04 Hz), 6.01 (d, 1H, J=5.85 Hz), 5.57 (d, 1H, J=5.85 Hz), 5.27 (d, 1H, J=5.11 Hz), 5.16 (m, 1H), 4.81 (s, 2H), 4.62 (m, 1H), 4.19 (m, 2H), 3.99 (m, 1H); 13C NMR (d6-DMSO): δ 162.0, 152.8, 149.5, 144.5, 133.7, 132.6, 125.2, 90.5, 87.6, 75.7, 72.2, 63.0, 33.9; Mp: 196-198° C.; HRMS calc. for C18H19N6O4S m/z=415.1200 (M+H), found 415.1155. to obtain a clear solution cooled to room temperature Upon standing at room temperature 37 was formed as a pale brown precipitate collected by filtration dried in vacuo (65% yield)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (Cyanomethyl)trimethyl-phosphonium iodide 36 (299 mg, 1.23 mmol) was added to a mixture of alcohol 35 (200 mg, 1.35 mmol), 6-mercaptopurine riboside (284 mg, 1.00 mmol), and DIPEA (0.25 mL) in propionitrile (3 mL). The mixture was heated at 90° C. and some drops of DMF were added to obtain a clear solution. The mixture was stirred overnight at 90° C., cooled to room temperature and water was added. Upon standing at room temperature, 37 was formed as a pale brown precipitate collected by filtration and dried in vacuo (65% yield). 1H NMR (d6-DMSO): δ 8.83, 8.72 (2×s, 2H), 8.21 (s, 1H), 7.70 (s, 1H), 7.54 (d, 1H, J=8.04 Hz), 7.31 (d, 1H, J=8.04 Hz), 6.01 (d, 1H, J=5.85 Hz), 5.57 (d, 1H, J=5.85 Hz), 5.27 (d, 1H, J=5.11 Hz), 5.16 (m, 1H), 4.81 (s, 2H), 4.62 (m, 1H), 4.19 (m, 2H), 3.99 (m, 1H); 13C NMR (d6-DMSO): δ 162.0, 152.8, 149.5, 144.5, 133.7, 132.6, 125.2, 90.5, 87.6, 75.7, 72.2, 63.0, 33.9; Mp: 196-198° C.; HRMS calc. for C18H19N6O4S m/z=415.1200 (M+H), found 415.1155. to obtain a clear solution cooled to room temperature Upon standing at room temperature 37 was formed as a pale brown precipitate collected by filtration dried in vacuo (65% yield)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzimidazole analogs were synthesized by a Mitsunobu coupling (Zaragoza, F. Tetrahedron 2001, 57, 5451-5454 and Zaragoza, F.; Stephensen, H. J. Org. Chem. 2001, 66, 2518-2521) of 6-mercaptopurine riboside with benzimidazole-methyl alcohol (Kimura, T.; Takase, Y.; Hayashi, K.; Tanaka, H.; Ohtsuka, I.; Saeki, T.; Kogushi, M.; Yamada, T.; Fujimori, T.; Saitou, I.; Akasaka, K. J. Med. Chem. 1993, 36, 1630-1640), in the presence of (cyanomethyl)trimethylphosphonium iodide (36) and diisopropylethylamine (DIPEA) in propionitrile (Scheme 4). After refluxing of this mixture for 18 hr, water was added and the product precipitated. The direct use of alcohol 34 and 35 is an advantage of this method compared to the previous reactions. (Temple, C.; Kussner, C. L.; Montgomery, J. A. J. Org. Chem. 1968, 11, 41-43). These alcohols were prepared from reduction of the appropriate esters via standard procedures. (Sun, Q.; Gatto, B.; Yu, C.; Liu, A.; Liu, L. F.; LaVoie, E. J. J. Med. Chem. 1995, 38, 3638-3644). After refluxing of this mixture for 18 hr the product precipitated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution containing 1-formyl-4-(2-hydroxyethyl)piperazine (1.90 g, 12 mmol), 2-mercaptobenzimidazole (1.50 g, 10 mmol), and N,N-diisopropylethylamine (1.80 g, 14 mmol) in propionitrile (16 mL), cyanomethyltrimethylphosphonium iodide (2.80 g, 11.5 mmol) was added under argon, and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was poured into water (100 mL), and the liquid was subjected to extraction with chloroform (100 mL×3) . The organic layer was washed with saturated brine, followed by drying over sodium sulfate anhydrate and removing the solvent through filtration. The thus-formed crude product was crystallized from acetone-diethyl ether, thereby yielding 2.50 g of 1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine (yield: 86%) as a colorless crystalline powder. was added under argon the mixture was refluxed for 2 hours After cooling the liquid was subjected to extraction with chloroform (100 mL×3) The organic layer was washed with saturated brine by drying over sodium sulfate anhydrate removing the solvent through filtration The thus-formed crude product was crystallized from acetone-diethyl ether

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (47.50 mg, 0.221 mmol), 3-fluoro-N-ethyl-4-(piperazin-1-yl)benzamide (69.3 mg, 0.276 mmol) and (cyanomethyl)trimethylphosphonium iodide (86 mg, 0.353 mmol) in Propiononitrile (Volume: 1.00 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.192 mL, 1.104 mmol) at 23° C. The reaction was stirred at 95° C. for 15 hr. The suspension was cooled to 23° C., concentrated via rotary evaporation, re-constituted in ACN (2.0 mL), stirred for 15 min, filtered, rinsed with ACN (3×1 mL) and dried in vacuo. The crude solid was re-suspended in ACN (2.0 mL), heated to reflux, cooled to 23° C., filtered, rinsed with ACN (3×2.0 mL) to provide N-ethyl-3-fluoro-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.069 g, 0.221 mmol, 70.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3 H) 2.54-2.64 (m, 4 H) 3.07-3.17 (m, 4 H) 3.21-3.28 (m, 2 H) 3.63 (s, 2 H) 6.71-6.76 (m, 1 H) 7.01-7.10 (m, 2 H) 7.55-7.64 (m, 3 H) 7.67 (dd, J=3.03, 1.52 Hz, 1 H) 8.32 (t, J=5.43 Hz, 1 H) 8.36 (d, J=1.77 Hz, 1 H) 11.58 (br. s., 1 H). ESI-MS: m/z 449.4 (M+H)+. mp=262.7-267.4° C. The suspension was cooled to 23° C. concentrated via rotary evaporation, re-constituted in ACN (2.0 mL) stirred for 15 min filtered rinsed with ACN (3×1 mL) dried in vacuo heated to reflux cooled to 23° C. filtered rinsed with ACN (3×2.0 mL)

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (50.00 mg, 0.232 mmol), 3-fluoro-N-methyl-4-(piperazin-1-yl)benzamide (68.9 mg, 0.290 mmol) and (cyanomethyl)trimethylphosphonium iodide (90 mg, 0.372 mmol) in Propiononitrile (Volume: 1.00 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.202 mL, 1.162 mmol) at 23° C. The reaction was stirred at 95° C. for 15 hr. The suspension was cooled to 23° C., concentrated via rotary evaporation, re-constituted in ACN (2.0 mL), stirred for 15 min, filtered, rinsed with ACN (3×1 mL) and dried in vacuo. The crude solid was re-suspended in ACN (2.0 mL), heated to reflux, cooled to 23° C., filtered, rinsed with ACN (3×2.0 mL) to provide 3-fluoro-N-methyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.081 g, 0.186 mmol, 80.0% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.54-2.63 (m, 4 H) 2.75 (d, J=4.55 Hz, 3 H) 3.08-3.17 (m, 4 H) 3.63 (s, 2 H) 6.71-6.75 (m, 1 H) 7.02-7.10 (m, 2 H) 7.53-7.63 (m, 3 H) 7.67 (dd, J=3.03, 1.52 Hz, 1 H) 8.29 (q, J=4.29 Hz, 1 H) 8.33-8.38 (m, 1 H) 11.56 (br. s., 1 H). ESI-MS: m/z 435.4 (M+H)+. mp=288.0-294.5° C. The suspension was cooled to 23° C. concentrated via rotary evaporation, re-constituted in ACN (2.0 mL) stirred for 15 min filtered rinsed with ACN (3×1 mL) dried in vacuo heated to reflux cooled to 23° C. filtered rinsed with ACN (3×2.0 mL)

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (7.20 mg, 0.033 mmol), N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide dihydrochloride (13.40 mg, 0.042 mmol) and (cyanomethyl)trimethylphosphonium iodide (13.02 mg, 0.054 mmol) in Propiononitrile (Volume: 0.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.029 mL, 0.167 mmol) at 23° C. The reaction was stirred at 95° C. for 18 hr. The suspension was cooled to 23° C., filtered, rinsed with ACN (3×1 mL) and dried in vacuo to provide N-ethyl-3-methyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.004 g, 0.01 mmol, 27.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3 H) 2.26 (s, 3 H) 2.53-2.65 (m, 4 H) 2.84-2.99 (m, 4 H) 3.20-3.27 (m, 2 H) 3.65 (s, 2 H) 6.71-6.76 (m, 1 H) 7.02 (d, J=8.34 Hz, 1 H) 7.07 (dd, J=3.54, 1.26 Hz, 1 H) 7.57-7.60 (m, 1 H) 7.60-7.66 (m, 2 H) 7.67 (dd, J=3.03, 1.52 Hz, 1 H) 8.22 (t, J=5.56 Hz, 1 H) 8.36 (d, J=1.52 Hz, 1 H) 11.58 (s, 1 H). ESI-MS: m/z 445.4 (M+H)+. mp=254.8-258.5° C. The suspension was cooled to 23° C. filtered rinsed with ACN (3×1 mL) dried in vacuo

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (75.00 mg, 0.348 mmol), N,3-dimethyl-4-(piperazin-1-yl)benzamide dihydrochloride (133 mg, 0.436 mmol) and (cyanomethyl)trimethylphosphonium iodide (136 mg, 0.558 mmol) in Propiononitrile (Volume: 2.00 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.425 mL, 2.439 mmol) at 23° C. The reaction was stirred at 95° C. for 15 hr. The suspension was cooled to 23° C., concentrated via rotary evaporation, re-constituted in ACN (2.0 mL), stirred for 15 min, filtered, rinsed with ACN (3×1 mL) and dried in vacuo. The crude solid was re-suspended in ACN (2.0 mL), heated to reflux, cooled to 23° C., filtered, rinsed with ACN (3×2.0 mL) to provide N,3-dimethyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.0594 g, 0.138 mmol, 39.6% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3 H) 2.53-2.66 (m, 4 H) 2.75 (d, J=4.55 Hz, 3 H) 2.86-2.96 (m, 4 H) 3.64 (s, 2 H) 6.71-6.76 (m, 1 H) 7.03 (d, J=8.34 Hz, 1 H) 7.07 (dd, J=3.66, 1.64 Hz, 1 H) 7.58 (d, J=1.77 Hz, 1 H) 7.59-7.66 (m, 2 H) 7.67 (dd, J=3.03, 1.52 Hz, 1 H) 8.19 (q, J=4.29 Hz, 1 H) 8.36 (d, J=1.52 Hz, 1 H) 11.58 (s, 1 H). ESI-MS: m/z 431.4 (M+H)+. mp=264.0-266.3° C. The suspension was cooled to 23° C. concentrated via rotary evaporation, re-constituted in ACN (2.0 mL) stirred for 15 min filtered rinsed with ACN (3×1 mL) dried in vacuo heated to reflux cooled to 23° C. filtered rinsed with ACN (3×2.0 mL)