2-methyl-2-pyrrolidin-1-ylpropanenitrile

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: To a solution of 2-methyl-2-(1-pyrrolidinyl)propanenitrile D4 (40 g; 289.85 mmol) in dry THF (0.8 L) under nitrogen, cooled at −78° C., was added dropwise a solution of phenyl lithium in dibutyl ether over 40 minutes (305.1 mL of a 1.9M solution; 579.70 mmol). After 2 h the reaction was allowed to reach room temperature and then stirred overnight at this temperature. The mixture was quenched at 0° C. with a saturated solution of NaHCO3 (0.8 L) and stirred for 15 minutes and diluted with water (ca. 0.6 L). The phases were separated and the aqueous back extracted with diethylether (2×1 L). The collected organics were dried over Na2SO4 and evaporated in vacuo to get 90 g of crude material as a yellow oil that was dissolved in methanol (1 L) at 0° C. and treated portionwise with sodium borohydride (21.93 g; 579.70 mmol). After 1 hour at 0° C. and then overnight at room temperature the mixture was cooled and quenched with water (ca. 0.5 L). Methanol was evaporated in vacuo and the aqueous phase, diluted with water (200 mL), was extracted with DCM (3×800 mL). The collected organics were dried over Na2SO4 and evaporated in vacuo to get the title product (51 g) as a yellow solid, used in step 2 without further purification. to reach room temperature The mixture was quenched at 0° C. with a saturated solution of NaHCO3 (0.8 L) stirred for 15 minutes diluted with water (ca. 0.6 L) The phases were separated the aqueous back extracted with diethylether (2×1 L) The collected organics were dried over Na2SO4 evaporated in vacuo to get 90 g of crude material as a yellow oil that After 1 hour at 0° C. quenched with water (ca. 0.5 L) Methanol was evaporated in vacuo the aqueous phase, diluted with water (200 mL) was extracted with DCM (3×800 mL) The collected organics were dried over Na2SO4 evaporated in vacuo

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

Procedure: The title compound (9.6 g, 63%) was prepared from pyrrolidine (8.35 ml, 0.1 mol), 2-butanone (8.96 g, 0.1 mol) and potassium cyanide (6.51 g, 0.1 mol) in water (50 ml) in a similar manner to that described in D4. 1H NMR (CDCl3) δ: 1.06 (3H, t, J=7.2 Hz), 1.45 (3H, s), 1.66-1.93 (6H, m), 2.70-2.75 (4H, m).

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

Procedure: The title compound (8.8 g, 100%) was prepared from pyrrolidine (8.96 ml, 0.107 mol), 3-pentanone (8.61 g, 0.1 mol) and potassium cyanide (6.51 g, 0.1 mol) in water (50 ml) in a similar manner to that described in D4. 1H NMR (CDCl3) δ: 0.95 (6H, t, J=7.6 Hz), 1.67-1.90 (8H, m), 2.67-2.72 (4H, m).

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

Procedure: The title compound (2.50 g, 76%) was prepared from pyrrolidine (1.42 g, 20 mmol), cyclopentanone (1.68 g, 20 mmol) and potassium cyanide (1.30 g, 20 mmol) in water (10 ml) in a similar manner to that described in D4. 1H NMR (CDCl3) δ: 1.80-1.90 (10H, m), 2.15 (2H, m), 2.71 (4H, m).

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-methyl-2-(1-pyrrolidinyl)propanenitrile D4 (10.7 g; 77.54 mmol) in THF (400 ml) at −70° C. under argon was added over 10 minutes a solution of phenyllithium in dibutylether (86.3 ml of a 1.8M solution; 155 mmol). The reaction mixture was stirred at −70° C. for 2 hours then allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled in ice as saturated aqueous sodium hydrogen carbonate (400 ml) was added. After stirring for a further 30 minutes the layers were separated, and the aqueous layer extracted with ether (200 ml). Combined organics were dried (MgSO4) and evaporated. The residual amber oil was dissolved in methanol (400 ml), cooled in ice and sodium borohydride (5.2 g; 137 mmol) added in four portions over 5 minutes. The reaction mixture was stirred with ice cooling for 30 minutes, the ice removed and stirred at room temperature for 1.5 hours. The mixture was cooled in ice as water (50 ml) was added prior to concentration in vacuo to approx 70 ml. The mixture was partitioned between 2N HCl (100 ml) and ethyl acetate (400 ml) and the organics extracted with 2N HCl (2×100 ml). Combined acidic aqueous layers were washed with ethyl acetate (200 ml), basified with 50% NaOH and extracted with DCM (3×150 ml). Combined DCM organic extracts were dried (Na2SO4) and evaporated in vacuo to afford the title compound as a colourless solid (15 g: 88%) 1H NMR (CDCl3), δ: 0.75 (3H, s), 0.99 (3H, s), 1.70-1.76 (4H, m), 1.80 (2H, bs), 2.65-2.70 (4H, m), 4.08 (1H, s), 7.20-7.42 (5H, m). to warm to room temperature stirred overnight was added After stirring for a further 30 minutes the layers were separated the aqueous layer extracted with ether (200 ml) Combined organics were dried (MgSO4) evaporated The residual amber oil was dissolved in methanol (400 ml) cooled in ice The reaction mixture was stirred with ice cooling for 30 minutes the ice removed stirred at room temperature for 1.5 hours The mixture was cooled in ice as water (50 ml) was added to concentration in vacuo to approx 70 ml The mixture was partitioned between 2N HCl (100 ml) and ethyl acetate (400 ml) the organics extracted with 2N HCl (2×100 ml) Combined acidic aqueous layers were washed with ethyl acetate (200 ml) extracted with DCM (3×150 ml) Combined DCM organic extracts were dried (Na2SO4) evaporated in vacuo

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

Procedure: To a stirred, ice-cooled mixture of pyrrolidine (8.35 ml; 0.1 mol) and acetone (7.34 ml; 0.1 mol) was added a solution of potassium cyanide (6.51 g; 0.1 mol) in water (50 ml) dropwise over 10 min. After stirring at room temperature overnight, the crude reaction mixture was extracted with diethyl ether (2×250 ml) and the combined extracts washed with saturated brine (150 ml), dried (MgSO4), and evaporated under reduced pressure to afford the title product as a pale green liquid (10.7 g; 78%) which was used without further purification. 1H NMR (CDCl3) δ: 1.51 (6H, s), 1.80-1.90 (4H, m), 2.70-2.80 (4H, m). To a stirred, ice-cooled the crude reaction mixture was extracted with diethyl ether (2×250 ml) the combined extracts washed with saturated brine (150 ml) dried (MgSO4) evaporated under reduced pressure

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

Procedure: To a solution of 2-methyl-2-(1-pyrrolidinyl)propanenitrile D4 (40 g; 289.85 mmol) in dry THF (0.8 L) under nitrogen, cooled at −78° C., was added dropwise a solution of phenyl lithium in dibutyl ether over 40 minutes (305.1 mL of a 1.9M solution; 579.70 mmol). After 2 h the reaction was allowed to reach room temperature and then stirred overnight at this temperature. The mixture was quenched at 0° C. with a saturated solution of NaHCO3 (0.8 L) and stirred for 15 minutes and diluted with water (ca. 0.6 L). The phases were separated and the aqueous back extracted with diethylether (2×1 L). The collected organics were dried over Na2SO4 and evaporated in vacuo to get 90 g of crude material as a yellow oil that was dissolved in methanol (1 L) at 0° C. and treated portionwise with sodium borohydride (21.93 g; 579.70 mmol). After 1 hour at 0° C. and then overnight at room temperature the mixture was cooled and quenched with water (ca. 0.5 L). Methanol was evaporated in vacuo and the aqueous phase, diluted with water (200 mL), was extracted with DCM (3×800 mL). The collected organics were dried over Na2SO4 and evaporated in vacuo to get the title product (51 g) as a yellow solid, used in step 2 without further purification. to reach room temperature The mixture was quenched at 0° C. with a saturated solution of NaHCO3 (0.8 L) stirred for 15 minutes diluted with water (ca. 0.6 L) The phases were separated the aqueous back extracted with diethylether (2×1 L) The collected organics were dried over Na2SO4 evaporated in vacuo to get 90 g of crude material as a yellow oil that After 1 hour at 0° C. quenched with water (ca. 0.5 L) Methanol was evaporated in vacuo the aqueous phase, diluted with water (200 mL) was extracted with DCM (3×800 mL) The collected organics were dried over Na2SO4 evaporated in vacuo

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

Procedure: The title compound (9.6 g, 63%) was prepared from pyrrolidine (8.35 ml, 0.1 mol), 2-butanone (8.96 g, 0.1 mol) and potassium cyanide (6.51 g, 0.1 mol) in water (50 ml) in a similar manner to that described in D4. 1H NMR (CDCl3) δ: 1.06 (3H, t, J=7.2 Hz), 1.45 (3H, s), 1.66-1.93 (6H, m), 2.70-2.75 (4H, m).

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

Procedure: The title compound (8.8 g, 100%) was prepared from pyrrolidine (8.96 ml, 0.107 mol), 3-pentanone (8.61 g, 0.1 mol) and potassium cyanide (6.51 g, 0.1 mol) in water (50 ml) in a similar manner to that described in D4. 1H NMR (CDCl3) δ: 0.95 (6H, t, J=7.6 Hz), 1.67-1.90 (8H, m), 2.67-2.72 (4H, m).