1,1,2-trimethylbenzo[e]indole

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To synthesize cypate, a mixture of 1,1,2-trimethyl-[1H]-benz[e]indole (40.0 g, 19.11 mmol) and 3-bromopropanoic acid (40.0 g, 26.15 mmol) in 1,2-dichlorobenzene (200 mL) was heated at 110° C. for 18 h. After the resulting mixture was cooled to room temperature, the precipitate was collected by filtration, followed by trituration in dichloromethane (DCM) to remove the un-reacted material, and then dried under vacuum to afford 1,1,2-trimethyl[1H]-benz[e]indole-3-propanoic acid. A solution of acetic anhydride (1.20 g, 11.75 mmol) in DCM (5 mL) was added dropwise to a cooled suspension of glutaconaldehyde dianil monohydrochloride (2.84 g, 9.97 mmol) and diisopropylethylamine (DIEA, 2.60 g, 20.11 mmol) in DCM (20 mL). The resulting clear solution was stirred for 1 h and added dropwise to a refluxing solution of 1,1,2-trimethyl[1H]-benz[e]indole-3-propanoic acid (8.2 g, 22.64 mmol) and sodium acetate (3.2 g, 39.01 mmol) in acetonitrile/water (95/5 mL). The mixture was refluxed for 16 h, cooled, filtered, and washed with acetonitrile, 5% HCl solution and ethyl ether. About 6 g (85%) of cypate was obtained. It was further purified by recrystallization from 30% acetonitrile in water. Mass calculated: 625; observed (ESI-MS): 625.34 [M]+. After the resulting mixture was cooled to room temperature the precipitate was collected by filtration to remove the un-reacted material dried under vacuum

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To synthesize cypate, a mixture of 1,1,2-trimethyl-[1H]-benz[e]indole (40.0 g, 19.11 mmol) and 3-bromopropanoic acid (40.0 g, 26.15 mmol) in 1,2-dichlorobenzene (200 mL) was heated at 110° C. for 18 h. After the resulting mixture was cooled to room temperature, the precipitate was collected by filtration, followed by trituration in dichloromethane (DCM) to remove the un-reacted material, and then dried under vacuum to afford 1,1,2-trimethyl[1H]-benz[e]indole-3-propanoic acid. A solution of acetic anhydride (1.20 g, 11.75 mmol) in DCM (5 mL) was added dropwise to a cooled suspension of glutaconaldehyde dianil monohydrochloride (2.84 g, 9.97 mmol) and diisopropylethylamine (DIEA, 2.60 g, 20.11 mmol) in DCM (20 mL). The resulting clear solution was stirred for 1 h and added dropwise to a refluxing solution of 1,1,2-trimethyl[1H]-benz[e]indole-3-propanoic acid (8.2 g, 22.64 mmol) and sodium acetate (3.2 g, 39.01 mmol) in acetonitrile/water (95/5 mL). The mixture was refluxed for 16 h, cooled, filtered, and washed with acetonitrile, 5% HCl solution and ethyl ether. About 6 g (85%) of cypate was obtained. It was further purified by recrystallization from 30% acetonitrile in water. Mass calculated: 625; observed (ESI-MS): 625.34 [M]+. After the resulting mixture was cooled to room temperature the precipitate was collected by filtration to remove the un-reacted material dried under vacuum

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,1,2-Trimethyl-1H-benz[e]indole, 100 g. was added with stirring to 500 mL of concentrated H2SO4. The mixture was heated at 180° C. for 1/2 h, cooled to 60° C. and poured onto 2 Kg ice. Cautiously 500 ml of 50% aqueous NaOH was added. After 24 hours at room temperature the solid was filtered off, and 500 mL of saturated aqueous Na2SO4 was added. The resulting solid precipitate was collected, added to the previously filtered solid, and recrystallized from 2 L of H2O. Yield 25 g after overnight vacuum drying at 50° C. The location of the sulfo group was determined as being the 7-position by proton nuclear magnetic resonance measurements. was added cooled to 60° C. After 24 hours at room temperature the solid was filtered off 500 mL of saturated aqueous Na2SO4 was added The resulting solid precipitate was collected added to the previously filtered solid recrystallized from 2 L of H2O Yield 25 g after overnight vacuum drying at 50° C

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,1,2-Trimethyl-1H-benz[e]indole, 100 g. was added with stirring to 500 mL of concentrated H2SO4. The mixture was heated at 180° C. for 1/2 h, cooled to 60° C. and poured onto 2 Kg ice. Cautiously 500 ml of 50% aqueous NaOH was added. After 24 hours at room temperature the solid was filtered off, and 500 mL of saturated aqueous Na2SO4 was added. The resulting solid precipitate was collected, added to the previously filtered solid, and recrystallized from 2 L of H2O. Yield 25 g after overnight vacuum drying at 50° C. The location of the sulfo group was determined as being the 7-position by proton nuclear magnetic resonance measurements. was added cooled to 60° C. After 24 hours at room temperature the solid was filtered off 500 mL of saturated aqueous Na2SO4 was added The resulting solid precipitate was collected added to the previously filtered solid recrystallized from 2 L of H2O Yield 25 g after overnight vacuum drying at 50° C

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

Procedure: A mixture of 1,1,2-trimethyl-[1H]-benz[e]indole (10.0 g, 47.8 mmol) and 3-bromopropanoic acid (7.3 g, 47.8 mmol) in 1,2-dichlorobenzene (50 mL) was heated with stirring at 110° c. for 18 h. After the resulting mixture was cooled to room temperature, the precipitated was collected by filtration, triturated with DCM thoroughly, and dried under vacuum to afford 15.2 g of light brown powder (88%). ESI-MS: observed for [MH]+ 281.31. was heated the precipitated was collected by filtration triturated with DCM thoroughly dried under vacuum

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

Procedure: A mixture of 1,1,2-trimethyl-[1H]-benz[e]indole (10.0 g, 47.8 mmol) and 3-bromopropanoic acid (7.3 g, 47.8 mmol) in 1,2-dichlorobenzene (50 mL) was heated with stirring at 110° c. for 18 h. After the resulting mixture was cooled to room temperature, the precipitated was collected by filtration, triturated with DCM thoroughly, and dried under vacuum to afford 15.2 g of light brown powder (88%). ESI-MS: observed for [MH]+ 281.31. was heated the precipitated was collected by filtration triturated with DCM thoroughly dried under vacuum

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

Procedure: Ethyl iodide (1.1 g, 7.2 mmol) was added to an acetonitrile solution (40 ml) of 1,1,2-trimethylbenz[e]indole (1) (1.0 g, 4.8 mmol, Daiichi Pure Chemicals Co., Ltd.), and then the mixture was heated under reflux for 2 days. The reaction mixture was concentrated under reduced pressure, and ether (80 ml) was added to the residue. The resulting solid was repeatedly washed with ether to obtain the title compound (2) as a dark violet solid (1.6 g, 91%). mp. 213-218° C. (decomposition). the mixture was heated under reflux for 2 days The reaction mixture was concentrated under reduced pressure, and ether (80 ml) was added to the residue The resulting solid was repeatedly washed with ether

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,1,2-Trimethyl-1H-benz[e]indole, 100 g. was added with stirring to 500 mL of concentrated H2SO4. The mixture was heated at 180° C. for 1/2 h, cooled to 60° C. and poured onto 2 Kg ice. Cautionsly 500 ml of 50% aqueous NaOH was added. After 24 hours at room temperature the solid was filtered off, and 500 mL of saturated aqueous Na2SO4 was added. The resulting solid precipitate was collected, added to the previously filtered solid, and recrystallized from 2 L of H2O. Yield 25 g after overnight vacuum drying at 50° C. The location of the sulfo group was determined as being the 7-position by proton nuclear magnetic resonance measurements. was added cooled to 60° C. After 24 hours at room temperature the solid was filtered off 500 mL of saturated aqueous Na2SO4 was added The resulting solid precipitate was collected added to the previously filtered solid recrystallized from 2 L of H2O Yield 25 g after overnight vacuum drying at 50° C

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1,1,2-trimethyl[1H]-benz[e]indole (10.0 g, 47.8 mmol) and 3-bromopropanoic acid (7.3 g, 47.8 mmol) in 1,2-dichlorobenzene (50 mL) was heated with stirring at 110° C. for 18 h. After the resulting mixture was cooled to room temperature, the precipitated was collected by filtration, triturated with DCM thoroughly, and dried under vacuum to afford 15.2 g of light brown powder (88%). ESI-MS: observed for [MH]+281.31. was heated After the resulting mixture was cooled to room temperature the precipitated was collected by filtration triturated with DCM thoroughly dried under vacuum

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

Procedure: 1,1,2-Trimethylbenzo[e]indole (1.0 g, 4.8 mmol) and 1,4-butane sultone (0.50 mL, 4.8 mmol) were heated for 2.5 h at 130° C., filtered off after cooling, washed with acetone and dried for 3 h at 100° C. Yield: 1.13 g (70%) gray-white solid, melting point 263° C. (Lit. review: H. Langhals, C. Haritoglou, Der Ophthalmologe 2009, 106, 16-20: 266° C.). IR (ATR): {tilde over (ν)}=3435 (m), 2939 (w), 1636 (w), 1584 (w), 1523 (w), 1468 (m), 1199 (s), 1034 (s), 872 (w), 824 (m), 791 (w), 758 (m), 737 cm−1 (w). 1H NMR (400 MHz, CD3OD): δ=8.32 (d, 1H, Haromatic, 3J=8.5 Hz), 8.24 (d, 1H, Haromatic, 3J=8.9 Hz), 8.16 (d, 1H, Haromatic, 3J=8.2 Hz), 8.06 (d, 1H, Haromatic, 3J=9.0 Hz), 7.80 (ddd, 1H, Haromatic, 4J=1.3 Hz, 3J=6.9 Hz, 3J=8.4 Hz), 7.71 (ddd, 1H, Haromatic, 4J=1.1 Hz, 3J=6.9 Hz, 3J=8.1 Hz), 4.70-4.64 (m, 2H, NCH2), 2.91 (t, 2H, CH2SO3−, 3J=7.1 Hz), 2.26-2.18 (m, 2H, CH2), 2.03-1.94 (m, 2H, CH2), 1.84 (s, 6H, 2×CH3), 1.30 ppm (s, 3H, CH3). 13C NMR (100 MHz, CD3OD): δ=196.6, 138.7, 137.5, 134.1, 131.3, 129.9, 128.5, 127.9, 127.5, 123.2, 112.7, 56.1, 49.9, 26.4, 23.0, 22.1, 21.2 ppm. HRMS (ESI) (C19H24NO3S): calculated 346.1471. found 346.1473, Δ=0.2 mmu. filtered off after cooling washed with acetone dried for 3 h at 100° C Yield: 1.13 g (70%) gray-white solid, melting point 263° C. (Lit. review: H. Langhals, C. Haritoglou, Der Ophthalmologe 2009, 106, 16-20: 266° C.)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To synthesize cypate, a mixture of 1,1,2-trimethyl-[1H]-benz[e]indole (40.0 g, 19.11 mmol) and 3-bromopropanoic acid (40.0 g, 26.15 mmol) in 1,2-dichlorobenzene (200 mL) was heated at 110° C. for 18 h. After the resulting mixture was cooled to room temperature, the precipitate was collected by filtration, followed by trituration in dichloromethane (DCM) to remove the un-reacted material, and then dried under vacuum to afford 1,1,2-trimethyl[1H]-benz[e]indole-3-propanoic acid. A solution of acetic anhydride (1.20 g, 11.75 mmol) in DCM (5 mL) was added dropwise to a cooled suspension of glutaconaldehyde dianil monohydrochloride (2.84 g, 9.97 mmol) and diisopropylethylamine (DIEA, 2.60 g, 20.11 mmol) in DCM (20 mL). The resulting clear solution was stirred for 1 h and added dropwise to a refluxing solution of 1,1,2-trimethyl[1H]-benz[e]indole-3-propanoic acid (8.2 g, 22.64 mmol) and sodium acetate (3.2 g, 39.01 mmol) in acetonitrile/water (95/5 mL). The mixture was refluxed for 16 h, cooled, filtered, and washed with acetonitrile, 5% HCl solution and ethyl ether. About 6 g (85%) of cypate was obtained. It was further purified by recrystallization from 30% acetonitrile in water. Mass calculated: 625; observed (ESI-MS): 625.34 [M]+. After the resulting mixture was cooled to room temperature the precipitate was collected by filtration to remove the un-reacted material dried under vacuum