sodium;ethoxymethanedithioate

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tropine-3-mesylate (25 g, 0.114 mol) and sodium ethylxanthate (19.7 g, 0.137 mol) were added to stirred toluene (0.075 L) under nitrogen. The stirred mixture was maintained at 30° C. for 6 h. Water (0.05 L) was added and after 15 min stirring the phases were separated. The toluene phase, containing the title compound, was used directly in the preparation of tropine-3-thiol as in Step 4b. were separated The toluene phase, containing the title compound was used directly in the preparation of tropine-3-thiol as in Step 4b

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tropine-3-mesylate (25 g, 0.114 mol) and sodium ethylxanthate (19.7 g, 0.137 mol) were added to stirred toluene (0.075 L) under nitrogen. The stirred mixture was maintained at 30° C. for 6 h. Water (0.05 L) was added and after 15 min stirring the phases were separated. The toluene phase, containing the title compound, was used directly in the preparation of tropine-3-thiol as in Step 4b. were separated The toluene phase, containing the title compound was used directly in the preparation of tropine-3-thiol as in Step 4b

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

Procedure: Tropine-3-mesylate (243.6 g, 1.11 mol) and sodium ethylxanthate (245.1 g, 1.70 mol) were added to stirred toluene (1.25 L) at 36° C. under nitrogen. The mixture was reheated to 35-37° C. (from 30° C.) where it was maintained overnight (˜18 h). The oilbath was removed and water (500 mL) added. After 2 h stirring the mixture was filtered and the phases separated. The toluene phase was washed with deionised water (1×500 mL, 1×300 mL). The yield was found to be 192.36 g, 70.6%, based on 14.42% w/w in solution, by LC analysis against a reference standard. The solution was stored at 4° C. prior to use in Step 4a. was reheated to 35-37° C. (from 30° C.) where it was maintained overnight (˜18 h) The oilbath was removed water (500 mL) added was filtered the phases separated The toluene phase was washed with deionised water (1×500 mL, 1×300 mL) was stored at 4° C.

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

Procedure: Tropine-3-mesylate (243.6 g, 1.11 mol) and sodium ethylxanthate (245.1 g, 1.70 mol) were added to stirred toluene (1.25 L) at 36° C. under nitrogen. The mixture was reheated to 35-37° C. (from 30° C.) where it was maintained overnight (˜18 h). The oilbath was removed and water (500 mL) added. After 2 h stirring the mixture was filtered and the phases separated. The toluene phase was washed with deionised water (1×500 mL, 1×300 mL). The yield was found to be 192.36 g, 70.6%, based on 14.42% w/w in solution, by LC analysis against a reference standard. The solution was stored at 4° C. prior to use in Step 4a. was reheated to 35-37° C. (from 30° C.) where it was maintained overnight (˜18 h) The oilbath was removed water (500 mL) added was filtered the phases separated The toluene phase was washed with deionised water (1×500 mL, 1×300 mL) was stored at 4° C.

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

Procedure: A mixture of ethyl 3-amino-2-[(2'-cyanobiphenyl-4-yl)methyl]aminobenzoate (5.6 g) and sodium O-ethyl dithiocarbonate (7.3 g) in ethanol (50 ml) was heated for 8 hours under reflux. The reaction mixture was concentrated and the residue was dissolved in water. The solution was adjusted to pH 3-4 with hydrochloric acid. Precipitating crystals were collected by filtration, followed by recrystallization from ethanol to afford yellow crystals (5.0 g, 80%), m.p. 225°-227° C. was heated for 8 hours under reflux The reaction mixture was concentrated the residue was dissolved in water Precipitating crystals were collected by filtration followed by recrystallization from ethanol

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tropine-3-mesylate (25 g, 0.114 mol) and sodium ethylxanthate (19.7 g, 0.137 mol) were added to stirred toluene (0.075 L) under nitrogen. The stirred mixture was maintained at 30° C. for 6 h. Water (0.05 L) was added and after 15 min stirring the phases were separated. The toluene phase, containing the title compound, was used directly in the preparation of tropine-3-thiol as in Step 4b. were separated The toluene phase, containing the title compound was used directly in the preparation of tropine-3-thiol as in Step 4b

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

Procedure: Tropine-3-mesylate (243.6 g, 1.11 mol) and sodium ethylxanthate (245.1 g, 1.70 mol) were added to stirred toluene (1.25 L) at 36° C. under nitrogen. The mixture was reheated to 35-37° C. (from 30° C.) where it was maintained overnight (˜18 h). The oilbath was removed and water (500 mL) added. After 2 h stirring the mixture was filtered and the phases separated. The toluene phase was washed with deionised water (1×500 mL, 1×300 mL). The yield was found to be 192.36 g, 70.6%, based on 14.42% w/w in solution, by LC analysis against a reference standard. The solution was stored at 4° C. prior to use in Step 4a. was reheated to 35-37° C. (from 30° C.) where it was maintained overnight (˜18 h) The oilbath was removed water (500 mL) added was filtered the phases separated The toluene phase was washed with deionised water (1×500 mL, 1×300 mL) was stored at 4° C.

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tropine-3-mesylate (25 g, 0.114 mol) and sodium ethylxanthate (19.7 g, 0.137 mol) were added to stirred toluene (0.075 L) under nitrogen. The stirred mixture was maintained at 30° C. for 6 h. Water (0.05 L) was added and after 15 min stirring the phases were separated. The toluene phase, containing the title compound, was used directly in the preparation of tropine-3-thiol as in Step 4b. were separated The toluene phase, containing the title compound was used directly in the preparation of tropine-3-thiol as in Step 4b

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

Procedure: Tropine-3-mesylate (243.6 g, 1.11 mol) and sodium ethylxanthate (245.1 g, 1.70 mol) were added to stirred toluene (1.25 L) at 36° C. under nitrogen. The mixture was reheated to 35-37° C. (from 30° C.) where it was maintained overnight (˜18 h). The oilbath was removed and water (500 mL) added. After 2 h stirring the mixture was filtered and the phases separated. The toluene phase was washed with deionised water (1×500 mL, 1×300 mL). The yield was found to be 192.36 g, 70.6%, based on 14.42% w/w in solution, by LC analysis against a reference standard. The solution was stored at 4° C. prior to use in Step 4a. was reheated to 35-37° C. (from 30° C.) where it was maintained overnight (˜18 h) The oilbath was removed water (500 mL) added was filtered the phases separated The toluene phase was washed with deionised water (1×500 mL, 1×300 mL) was stored at 4° C.

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tropine-3-mesylate (25 g, 0.114 mol) and sodium ethylxanthate (19.7 g, 0.137 mol) were added to stirred toluene (0.075 L) under nitrogen. The stirred mixture was maintained at 30° C. for 6 h. Water (0.05 L) was added and after 15 min stirring the phases were separated. The toluene phase, containing the title compound, was used directly in the preparation of tropine-3-thiol as in Step 4b. were separated The toluene phase, containing the title compound was used directly in the preparation of tropine-3-thiol as in Step 4b

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

Procedure: Tropine-3-mesylate (243.6 g, 1.11 mol) and sodium ethylxanthate (245.1 g, 1.70 mol) were added to stirred toluene (1.25 L) at 36° C. under nitrogen. The mixture was reheated to 35-37° C. (from 30° C.) where it was maintained overnight (˜18 h). The oilbath was removed and water (500 mL) added. After 2 h stirring the mixture was filtered and the phases separated. The toluene phase was washed with deionised water (1×500 mL, 1×300 mL). The yield was found to be 192.36 g, 70.6%, based on 14.42% w/w in solution, by LC analysis against a reference standard. The solution was stored at 4° C. prior to use in Step 4a. was reheated to 35-37° C. (from 30° C.) where it was maintained overnight (˜18 h) The oilbath was removed water (500 mL) added was filtered the phases separated The toluene phase was washed with deionised water (1×500 mL, 1×300 mL) was stored at 4° C.

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

Procedure: Scheme 3 depicts the synthesis of 6-methylsulfanyl-3,4-dihydro-isoquinoline (XII). 3-Amino-benzoic acid (IV) is diazotized, reacted with sodium ethyl xanthate, followed by saponification, and is alkylated with dimethyl sulfate to give 3-methylsulfanyl-benzoic acid (V). This acid is reduced with Red-Al® (sodium bis (2-methoxyethoxy) aluminum hydride in toluene, Aldrich, Milwaukee, Wis., USA) to yield the alcohol (VI) which is converted to a benzyl chloride (VII) using thionyl chloride. The benzyl nitrile compound (VIII) is synthesized by treating (VII) with potassium cyanide in the presence of 18-crown-6. Standard reduction conditions (e.g., Raney nickel) gives phenethyl carbamate (IX), and deprotection yields the phenethylamine (X). (XI) is obtained by treating (X) with ethyl formate, followed by ring closure using phosphorus oxychloride to give the desired dihydroisoquinoline (XII).