2-(1-methylpyrrolidin-2-yl)ethanol

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

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

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

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

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

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: 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (405 mg, 1.72 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethanol (178 mg, 1.38 mmol), PPh3 (451 mg, 1.72 mmol), THF (8 ml) and DIAD (348 mg, 1.72 mmol) were reacted together according to general procedure C. The crude product was subjected to chromatography on alumina eluting with ethyl acetate:heptane (50:50) to provide the title compound (130 mg, 27%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.87 (d, 2H), 4.09-3.95 (m, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.09 (m, 1H), 2.40 (s, 2H), 2.35 (s, 3H), 2.30-1.99 (m, 6H), 1.96 (s, 6H), 1.93-1.63 (m, 6H).

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

Procedure: 4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (405 mg, 1.72 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethanol (178 mg, 1.38 mmol), PPh3 (451 mg, 1.72 mmol), THF (8 ml) and DIAD (348 mg, 1.72 mmol) were reacted together according to general procedure C. The crude product was subjected to chromatography on alumina eluting with ethyl acetate:heptane (50:50) to provide the title compound (130 mg, 27%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δ7.21 (d, 2H), 6.87 (d, 2H), 4.09-3.95 (m, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.09 (m, 1H), 2.40 (s, 2H), 2.35 (s, 3H), 2.30-1.99 (m, 6H), 1.96 (s, 6H), 1.93-1.63 (m, 6H).

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To solution of compound A of Example 18 (63 mg, 0.16 mmol) in 1,4-dioxane (1.7 mL) at RT were added 4A sieves, triethylamine (0.91 mmol) and diphenylphosphoryl azide (0.41 mmol). The resulting mixture was warmed to 50° C. for 2 h, then to 80° C. and 2-(1-methylpyrrolidin-2-yl)-ethanol (0.82 mmol) was added. After 2 h, the mixture was cooled RT, filtered and water was added. The mixture was purified by reverse phase preparative HPLC. The appropriate fractions were collected and concentrated. The residue was further purified by silica gel column chromatography eluting with 1% NH4OH, 5% methanol in dichloromethane to afford the title compound (17 mg, 20%). LC/MS; (M+H)+=510.3 the mixture was cooled RT filtered water was added The mixture was purified by reverse phase preparative HPLC The appropriate fractions were collected concentrated The residue was further purified by silica gel column chromatography eluting with 1% NH4OH, 5% methanol in dichloromethane

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

Procedure: According to the procedure described for the synthesis of Example 5/step 1 5-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-1H-indole-2-carboxylic acid ethyl ester was synthesized from 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (commercially available) and 2-(1-methyl-pyrrolidin-2-yl)-ethanol (commercially available). The title compound was yielded in 38% as light brown foam. MS (m/e): 317.1 (MH+, 100%).

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

Procedure: To a dry THF solution (30 ml) of 2-(1-methyl-2-pyrrolidine)ethanol at -10° to 5° C. was dropwise added a 1.5M hexane solution of n-BuLi (16.0 ml, 24.0 mmol) over a period of 10 min. Stirring was continued for 30 min. To a mixture was then dropwise added at -5° to 5° C. a dry THF solution (20 ml) of indole-3-carboxylic acid chloride (4.20 g, 24.0 mmol) over a period of 45 min. The cooling bath was removed. After stirring overnight at room temperature, a reaction solution was poured onto a cold diluted hydrochloric acid, and the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted with saturated aqueous sodium bicarbonate to a pH of >10 and extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.91 g of the title compound as a yellow viscous material. A foamy solid; The cooling bath was removed After stirring overnight at room temperature a reaction solution was poured onto a cold diluted hydrochloric acid the aqueous layer was washed with ethyl acetate extracted with ethyl acetate The organic layer was washed successively with water and saturated aqueous sodium chloride dried over anhydrous magnesium sulfate concentrated under reduced pressure