oxathiolane 2,2-dioxide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: Compound 13 was synthesized according to the procedure outlined above in Example 3 for the synthesis of the N-methyl-hydroxybenzoquinoline derivative 15. Compound 13 was then alkylated according to the general amino group alkylation procedure described above in Example 3, this time using 1,3-propane sultone as the alkylating agent rather than MeI, to give a 5-methoxybenzoquinoline-N-propanesulfonic acid intermediate 16 (1HNMR: CD3OD d 7.94 (d, 1 H, J=8.7 Hz), 7.65 (d, 1 H, J=8.4 Hz), 7.32 (t, 1 H), 7.27 (t, 1 H), 6.85 (s, 1 H), 4.89 (s, 3 H), 3.20 (m, 2 H), 3.08 (bt, 2 H, J=6 Hz), 2.91 (m, 2 H), 2.72 (t, 2 H, J=6.6 Hz), 2.33 (m, 2 H), 1.89 (m, 2 H). Subsequent methoxy group deprotection of compound 16 by the general boron tribromide procedure described above in Example 1 resulted in the 3-(5-hydroxybenzoquinolin-1-yl) propanesulfonic acid 17.

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

Procedure: To a solution of 4-phenylpyridine (15.5 g, 0.1 mol) in acetone (100 mL) was added 1,3-propane sultone (12.2 g, 0.1 mol) at room temperature. The mixture was then heated at reflux temperature overnight. The resultant suspension was cooled to room temperature. The solid was collected by filtration and washed with acetone. To a solution of the solid (31 g) in methanol (500 mL) was added sodium borohydride (10 g, 260 mmol) portionwise, and the mixture was stirred at room temperature for 2 h. Distilled water (50 mL) was added to destroy the excess of sodium borohydride. The mixture was diluted with methanol (200 ml), and neutralized with Amberlite IR-120 ion-exchange resin (H+ form, 300 g). A white precipitate was formed. The precipitate and the resin were removed by filtration and treated with distilled water (400 mL) at ˜100 ° C. The mixture was filtered and the residual resin was washed with hot distilled water (2×200 mL). The filtrates and washings were combined and concentrated to dryness. The residue was co-evaporated with methanol (3×200 mL), and then recrystallized from ethanol-water {8:2 (v/v)} to afford 4-phenyl-1-(3′-sulfopropyl)-1,2,3,6-tetrahydropyridine as white crystals (26 g, 93%). The 1H and 13C NMR spectra were in agreement with the structure. The mixture was then heated at reflux temperature overnight The solid was collected by filtration washed with acetone to destroy the excess of sodium borohydride The mixture was diluted with methanol (200 ml) A white precipitate was formed The precipitate and the resin were removed by filtration treated with distilled water (400 mL) at ˜100 ° C The mixture was filtered the residual resin was washed with hot distilled water (2×200 mL) concentrated to dryness recrystallized from ethanol-water {8:2 (v/v)}

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

Procedure: To a stirred solution of sodium azide (3.5 g, 50 mmol) in water (25 mL) was added a solution of 1,3-propane sultone (6.1 g, 50 mmol) in acetone (25 mL). The reaction mixture was stirred at room temperature for 24 h then concentrated to dryness. The resulting solid was suspended in diethyl ether (100 mL) and stirred at reflux for 1 h. The suspension was cooled to room temperature and the solid was collected by filtration, washed with acetone and diethyl ether, and dried under vacuum, affording of 3-azido-1-propanesulfonic acid (7.6 g, 80%). then concentrated to dryness stirred at reflux for 1 h The suspension was cooled to room temperature the solid was collected by filtration washed with acetone and diethyl ether dried under vacuum

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

Procedure: 600 mg (0.94 mmol) of 6-(4,5,6-triiodo-2,3-dimethyl-3H-3-indolyl)hexanoic acid was heated with 600 mg (4.7 mmol) of 1,3-propane sultone at 100° C. for 40 minutes. The raw product was column purified (Silica gel 60, 0-40% methanol-chloroform) to give 300 mg of 3-[3-(5-carboxypentyl)-4,5,6-triiodo-2,3-dimethyl-3H-1-indoliumyl]-1-propanesulfonate: 7.39 (1H, s, arom.), 4.31 (2H, m, NCH2), 3.27 (3H, s, CH3), 2.34-2.02 (2H, m, CH2), 2.19 (2H, t, CH2CO), 1.98-1.65 (4H, m, CH2), 1.31 (3H, s, CH3), 1.43-1.00 (4H, m, (CH2)3), 0.62-0.35 (2H, m, CH2). purified (Silica gel 60, 0-40% methanol-chloroform)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (2.1 g, 80 wt %=69 mmol) was slurried in 10 ml dry THF. The suspension was cooled to 0° C. and a solution of ethyl-2-methylacetoacetate (10 g, 69 mmol) in 10 ml dry THF was added dropwise. The solution was stirred at room temperature for one h. A solution of 1,3-propanesultone (8.42 g, 69 mmol) in 10 ml dry THF was added dropwise. Once the addition was complete, the solution was stirred for two h at 40° C. The solution was evaporated to dryness. The residue was dissolved in 100 ml water. The aqueous solution was extracted twice with ethylacetate, then 100 ml concentrated HCl was added and the solution was refluxed for two hours. The solvent was evaporated in vacuum. The residue was purified by column chromatography (silica, methanol/dichloromethane) to give 4-methyl-5-oxohexane sulfonic acid. Yield 10 g; MS (ESI−): 193.2 [M]− Once the addition the solution was stirred for two h at 40° C The solution was evaporated to dryness The residue was dissolved in 100 ml water The aqueous solution was extracted twice with ethylacetate 100 ml concentrated HCl was added the solution was refluxed for two hours The solvent was evaporated in vacuum The residue was purified by column chromatography (silica, methanol/dichloromethane)

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

Procedure: Compound 13 was synthesized according to the procedure outlined above in Example 3 for the synthesis of the N-methyl-hydroxybenzoquinoline derivative 15. Compound 13 was then alkylated according to the general amino group alkylation procedure described above in Example 3, this time using 1,3-propane sultone as the allylating agent rather than MeI, to give a 5-methoxybenzoquinoline-N-propanesulfonic acid intermediate 16 (1HNMR: CD3OD d 7.94 (d, 1 H, 3=8.7 Hz), 7.65 (d, 1 H, J 8.4 Hz), 7.32 (t, 1 H), 7.27 (t, 1 H), 6.85 (s, 1 A), 4.89 (s, 3 H), 3.20 (m, 2 H), 3.08 (bt, 2 H, J=6 Hz), 2.91 (m, 2 H), 2.72 (t, 2 H, J=6.6 Hz), 2.33 (m, 2 H), 1.89 (m, 2 H). Subsequent methoxy group deprotection of compound 16 by the general boron tribronide procedure described above in Example I resulted in the 3-(5-hydroxybenzoquinolin-1-yl) propanesulfonic acid 17.

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

Procedure: N-methyl piperizine (4.68 g) was dissolved in isopropanol (25 ml) and treated with 1,3-propanesultone (5.7 g) with cooling to maintain the temperature of the reaction below 50° C. The reaction mixture was allowed to stand at room temperature overnight, then diluted with ether and the white solid filtered. On standing, the white solid became a sticky semi-solid (7.1 g). Mass spec MH+ (found)=223 MH+ (calc)=223. with cooling to maintain the temperature of the reaction below 50° C the white solid filtered

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

Procedure: The crude 1-[1-(4-chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-ol (3.5 g, 11.22 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 471 mg, 11.79 mmol) in dimethylformamide (25 mL). After stirring for 30 min at room temperature 1,3-propanesultone (1.44 g, 11.79 mmol) was added dropwise. The reaction mixture was stirred over night at room temperature. The dimethylformamide was removed in vacuo. The crude product (8.4 g) was used for the next step without further purification. was added dropwise The dimethylformamide was removed in vacuo The crude product (8.4 g) was used for the next step without further purification

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

Procedure: The crude 1-[1-(4-chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-ol (3.5 g, 11.22 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 471 mg, 11.79 mmol) in dimethylformamide (25 mL). After stirring for 30 min at room temperature 1,3-propanesultone (1.44 g, 11.79 mmol) was added dropwise. The reaction mixture was stirred over night at room temperature. The dimethylformamide was removed in vacuo. The crude product (8.4 g) was used for the next step without further purification. was added dropwise The dimethylformamide was removed in vacuo The crude product (8.4 g) was used for the next step without further purification

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

Procedure: A solution of 1,3-propanesultone (2.5 g, 20 mmol) in 2-butanone (10 mL) was added to a solution of 3-methyl-3-ethyl-3-propylamine in toluene (total volume: 30 mL). The mixture was heated to reflux for 5 hours then was cooled to room temperature. The solid was collected by suction-filtration and rinsed with acetone (2×5 mL). The solid was dried overnight at 45° C. in the vacuum oven. The title compound was obtained as a fine white solid (3.63 g, 16.3 mmol, 33% overall yield). 1H NMR (500 MHz, DMSO-d6) δ 0.79 (t, J=7.3 Hz, 6H), 1.15 (s, 3H), 1.53-1.59 (m, 4H), 1.97-2.00 (m, 2H), 2.89 (t, J=7.1 Hz, 2H), 3.03 (t, J=7.6 Hz, 2H); 13C NMR (125 MHz, DMSO-d6) δ 6.8, 20.2, 21.9, 27.7, 39.7, 48.2, 63.3 ES-MS 224; (M+H) The mixture was heated to reflux for 5 hours The solid was collected by suction-filtration rinsed with acetone (2×5 mL) The solid was dried overnight at 45° C. in the vacuum oven