2-methyl-2-pyrrolidin-1-ylpropan-1-ol

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

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

Procedure: Crude 2-methyl-2-pyrrolidin-1-yl-propan-1-ol (0.849 g, 5.94 mmol, 1 eq) was suspended in dry acetonitrile (30 mL) under Ar. Triethylamine (1.4 mL, 10 mmol, 1.7 eq) was added followed by the addition of toluenesulfonyl chloride (1.05 g, 5.50 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 1 hour. After 4 hours, the reaction was treated with 2-methyl-3-benzyloxycarbonyl-5-hydroxyindole (1.5 g; 5.5 mmol, 1 eq) and potassium carbonate (1.38 g, 10 mmol, 1.7 eq.). The reaction was heated to reflux and followed by TLC (ethyl acetate/methanol/triethylamine 87/10/3). After 23 hours, the reaction was loaded directly on silica gel and chromatographed (ethyl acetate/methanol/triethylamine 87/10/3). Impure product was further purified by reverse-phase prep-HPLC 10-100% Acetonitrile/water, 0.1% TFA. 0.040 g (5% yield) of the indole-amine was obtained as a brown semisolid: LC/MS (ESI+) 407 (M+1), Anal. (C24H30N2O2.TFA.1.0H2O) C, H, N. After 4 hours The reaction was heated to reflux After 23 hours chromatographed (ethyl acetate/methanol/triethylamine 87/10/3) Impure product was further purified by reverse-phase prep-HPLC 10-100% Acetonitrile/water, 0.1% TFA

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methyl-2-pyrrolidin-1-yl-propionic acid ethyl ester (2.00 g, 10.8 mmol, 1 eq) was suspended in dry THF (20 mL) under Ar. Methanol (2.0 mL, 50 mmol, 5.0 eq) was added followed by cooling to 4° C. and the addition of lithium borohydride (25 mL of 2M, 50 mmol, 5.0 eq). The reaction mixture was stirred and allowed to warm to room temperature. After 18 hours, the reaction was quenched with methanol, then aqueous NaOH, and extracted with CH2Cl2 (3×). The combined organic extracts were washed with brine and dried over Na2SO4. After removing the solvent, the crude residue was used in the next step. to warm to room temperature the reaction was quenched with methanol aqueous NaOH, and extracted with CH2Cl2 (3×) The combined organic extracts were washed with brine dried over Na2SO4 After removing the solvent

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

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

Procedure: The title compound was prepared in 17% yield from methyl vanillate and 2-methyl-2-(1-pyrrolidinyl)propanol (Example 188, Part A) by a essentially following the procedure outlined in Example 193, Part A.

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

Procedure: A solution of 2-amino-2-methyl-1-propanol (15 g, 168.3 mmol), 1,4-dibromobutane (18.2 g, 84.1 mmol), and K2CO3 (48.8 g, 353.4 mmol) in 1 L of THF was heated at 60° C. for 4.5 days. After cooling to ambient temperature, the reaction mixture was filtered and concentrated in vacuo. Flash chromatography (SiO2; 94:4:2 EtOAc/MeOH/TEA) afforded 8.21 g (57.3 mmol; 34%) of the title product as a pale yellow oil. A small sample was dissolved in EtOAc and treated with one equivalent of oxalic acid in a method similar to Example 1, Part C. the reaction mixture was filtered concentrated in vacuo

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

Procedure: 2-Methyl-2-pyrrolidin-1-ylpropan-1-ol (0.3776 g, 2.0682 mmol) was taken up in anhydrous DMF (5 mL). Sodium hydride (0.083 g of a 60% dispersion, 2.0682 mmol) was added. The reaction was stirred at RT until gas evolution was complete. 1-Chloro-2-methoxy-4-nitrobenzene (0.3578 g, 2.0682 mmol) was added. The reaction was heated to 80° C. and stirred for 72 h. Cooled to RT and diluted with EtOAc, (50 mL) and washed with water (3×50 mL). Organics were dried over MgSO4, filtered and concentrated. Crude product was purified by chromatatron (100% CH2Cl2 to 95:5 CH2Cl2:MeOH) to give 0.075 g (0.2551 mmol, 12%) of the product. 1H NMR (CDCl3) δ 7.81 (d, 1H, J=8.8 Hz), 7.73 (s, 1H), 7.15 (d, 1H, J=8.8 Hz), 3.88 (s, 3H), 2.76 (s, 2H), 2.68 (bs, 4H), 1.75 (bs, 4H), 1.38 (s, 6H). The reaction was heated to 80° C. stirred for 72 h Cooled to RT washed with water (3×50 mL) Organics were dried over MgSO4 filtered concentrated Crude product was purified by chromatatron (100% CH2Cl2 to 95:5 CH2Cl2:MeOH)

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

Procedure: Ethyl 2-methyl-2-pyrrolidin-1-ylpropanoate (0.6162 g, 3.3308 mmol) was taken up in dry THF (5 mL). A 1M solution of LAH in THF (3.7 mL, 3.6639 mmol) was added drop wise. The reaction was warmed to 50° C. and stirred for 18 h. Cooleed to 0° C. in an ice bath and methanol (5 mL) was added slowly. The reaction was diluted with water (50 mL) and extracted with Et2O (2×50 mL). The organics were concentrated by blowing a slow stream of N2 over the flask to give 0.3578 g (2.0682 mmol, 62%) of the product as a light brown oil. 1H NMR (CDCl3) δ 3.22 (s, 2H), 2.61 (bs, 4H), 1.79 (bs, 4H), 1.01 (s, 6H). extracted with Et2O (2×50 mL) The organics were concentrated

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

Procedure: Crude 2-methyl-2-pyrrolidin-1-yl-propan-1-ol (0.849 g, 5.94 mmol, 1 eq) was suspended in dry acetonitrile (30 mL) under Ar. Triethylamine (1.4 mL, 10 mmol, 1.7 eq) was added followed by the addition of toluenesulfonyl chloride (1.05 g, 5.50 mmol, 1.0 eq). The reaction mixture was stirred at room temperature for 1 hour. After 4 hours, the reaction was treated with 2-methyl-3-benzyloxycarbonyl-5-hydroxyindole (1.5 g; 5.5 mmol, 1 eq) and potassium carbonate (1.38 g, 10 mmol, 1.7 eq.). The reaction was heated to reflux and followed by TLC (ethyl acetate/methanol/triethylamine 87/10/3). After 23 hours, the reaction was loaded directly on silica gel and chromatographed (ethyl acetate/methanol/triethylamine 87/10/3). Impure product was further purified by reverse-phase prep-HPLC 10-100% Acetonitrile/water, 0.1% TFA. 0.040 g (5% yield) of the indole-amine was obtained as a brown semisolid: LC/MS (ESI+) 407 (M+1), Anal. (C24H30N2O2.TFA.1.0H2O) C, H, N. After 4 hours The reaction was heated to reflux After 23 hours chromatographed (ethyl acetate/methanol/triethylamine 87/10/3) Impure product was further purified by reverse-phase prep-HPLC 10-100% Acetonitrile/water, 0.1% TFA

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methyl-2-pyrrolidin-1-yl-propionic acid ethyl ester (2.00 g, 10.8 mmol, 1 eq) was suspended in dry THF (20 mL) under Ar. Methanol (2.0 mL, 50 mmol, 5.0 eq) was added followed by cooling to 4° C. and the addition of lithium borohydride (25 mL of 2M, 50 mmol, 5.0 eq). The reaction mixture was stirred and allowed to warm to room temperature. After 18 hours, the reaction was quenched with methanol, then aqueous NaOH, and extracted with CH2Cl2 (3×). The combined organic extracts were washed with brine and dried over Na2SO4. After removing the solvent, the crude residue was used in the next step. to warm to room temperature the reaction was quenched with methanol aqueous NaOH, and extracted with CH2Cl2 (3×) The combined organic extracts were washed with brine dried over Na2SO4 After removing the solvent