N-methyl-2-pyrrolidin-1-ylethanamine

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: To a solution of 0.34 g of N-(2-(1-pyrrolidinyl)ethyl)methylamine in 5 ml of dimethylformamide, 0.045 g of NaH (60% dispersion in mineral oil) were added under nitrogen and the mixture was stirred at room temperature for half an hr; a solution of 0.50 g of 3β-(2-tosyloxyethylthio)-17β-(3-furyl)-5β-androstan-14β-ol, prepared as described in Ex. 51, in 2 ml of dimethylformamide was added, the mixture was stirred for another 4 hrs and then 7 ml of water were poured in. The residue was extracted with ethyl acetate, the organic solution was washed with water to neutral pH, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using methylene chloride/methanol 95/5 as eluant to give 0.28 g of the title compound (I-ca) as an amorphous solid. the mixture was stirred for another 4 hrs The residue was extracted with ethyl acetate the organic solution was washed with water to neutral pH dried over anhydrous sodium sulfate evaporated to dryness under reduced pressure The crude product was purified by flash-chromatography (SiO2)

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

Procedure: To a solution of 6-chloropyridine-3-sulfonylchloride (636 mg, 3 mmol; described in: Naegeli, C. et al. Helv. Chim. Actal. 1938, 21, 1746-1750) in methylene chloride (10 mL) was added methyl-(2-pyrrolidin-1-ylethyl)amine (384 mg, 3 mmol; described in: J. Amer. Chem. Soc. 1955, 77, 3632-3634) dissolved in methylene chloride (10 mL) dropwise. The reaction mixture was stirred over night at room temperature followed by the extraction with aqueous HCl (3%). The acidic water layer was alkalized with an aqueous saturated solution of NaHCO3 and extracted with methylene chloride. The organic phase was dried (Na2SO4) and evaporated in vacuo to give 0.75 gram (80% yield) of the title compound: MS (ES) m/z 304 (M++1). followed by the extraction with aqueous HCl (3%) extracted with methylene chloride The organic phase was dried (Na2SO4) evaporated in vacuo

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

Procedure: N-Methyl-2-(pyrrolidin-1-yl)ethylamine (0.086 g), tripotassium phosphate (0.17 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to a toluene (2.3 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzamido)-4-phenylbenzoate (0.15 g), followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then N-methyl-2-(pyrrolidin-1-yl)ethylamine (0.017 g), tripotassium phosphate (0.029 g), tris(dibenzylideneacetone)dipalladium(0) (2.5 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to the reaction mixture, followed by heating to reflux under a nitrogen atmosphere for 7 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then N-methyl-2-(pyrrolidin-1-yl)ethylamine (0.017 g), tripotassium phosphate (0.029 g), tris(dibenzylideneacetone)dipalladium(0) 2.5 mg, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (6.4 mg), and palladium(II) acetate (1.2 mg) were added to the reaction mixture, followed by heating to reflux under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, and water and chloroform were added thereto. The insoluble substance was removed by filtration. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.097 g of tert-butyl 2-(2-(benzyloxy)-5-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)benzamido)-4-phenylbenzoate. by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes by heating to reflux under a nitrogen atmosphere for 7 hours and 30 minutes The reaction mixture was cooled to room temperature by heating to reflux under a nitrogen atmosphere for 3 hours The reaction mixture was cooled to room temperature The insoluble substance was removed by filtration The organic layer was separated dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol]

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

Procedure: To a solution of 0.34 g of N-(2-(1-pyrrolidinyl)ethyl)methylamine in 5 ml of dimethylformamide, 0.045 g of NaH (60% dispersion in mineral oil) were added under nitrogen and the mixture was stirred at room temperature for half an hr; a solution of 0.50 g of 3β-(2-tosyloxyethylthio)-17β-(3-furyl)-5β-androstan-14β-ol, prepared as described in Ex. 51, in 2 ml of dimethylformamide was added, the mixture was stirred for another 4 hrs and then 7 ml of water were poured in. The residue was extracted with ethyl acetate, the organic solution was washed with water to neutral pH, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using methylene chloride/methanol 95/5 as eluant to give 0.28 g of the title compound (I-ca) as an amorphous solid. the mixture was stirred for another 4 hrs The residue was extracted with ethyl acetate the organic solution was washed with water to neutral pH dried over anhydrous sodium sulfate evaporated to dryness under reduced pressure The crude product was purified by flash-chromatography (SiO2)

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 Compound A of Example 98 (20 mg, 0.052 mmol) in DMF (1 mL) was added 1-(2-methylaminoethyl)-pyrrolidine (10 mg, 0.078 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (25 mg, 0.056 mmol). After 1 hr at 25° C. the mixture was purified directly by preparative HPLC, the product was collected, converted to its HCl salt and lyophilized to provide 22 mg (80%) of the title compound. MS: [M+H]+=491,493 (1:1);1H NMR (CD3OD): δ 8.27 (s, 1H), 7.83 (s, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.65–7.55 (m, 2H), 4.09 (s, 3H), 3.99–3.96 (m, 4H), 3.85 (br s, 2H), 3.58–3.51 (m, 2H), 3.29–3.15 (m, 5H), 2.19–2.07 (m, 4H). After 1 hr at 25° C. the mixture was purified directly by preparative HPLC the product was collected

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

Procedure: To a solution of Compound A of Example 98 (20 mg, 0.052 mmol) in DMF (1 mL) was added 1-(2-methylaminoethyl)-pyrrolidine (10 mg, 0.078 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (25 mg, 0.056 mmol). After 1 hr at 25° C. the mixture was purified directly by preparative HPLC, the product was collected, converted to its HCl salt and lyophilized to provide 22 mg (80%) of the title compound. MS: [M+H]+=491,493 (1:1);1H NMR (CD3OD): δ 8.27 (s, 1H), 7.83 (s, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.65–7.55 (m, 2H), 4.09 (s, 3H), 3.99–3.96 (m, 4H), 3.85 (br s, 2H), 3.58–3.51 (m, 2H), 3.29–3.15 (m, 5H), 2.19–2.07 (m, 4H). After 1 hr at 25° C. the mixture was purified directly by preparative HPLC the product was collected

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

Procedure: To a solution of Compound A of Example 98 (20 mg, 0.052 mmol) in DMF (1 mL) was added 1-(2-methylaminoethyl)-pyrrolidine (10 mg, 0.078 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (25 mg, 0.056 mmol). After 1 hr at 25° C. the mixture was purified directly by preparative HPLC, the product was collected, converted to its HCl salt and lyophilized to provide 22 mg (80%) of the title compound. MS: [M+H]+=491,493 (1:1);1H NMR (CD3OD): δ 8.27 (s, 1H), 7.83 (s, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.65–7.55 (m, 2H), 4.09 (s, 3H), 3.99–3.96 (m, 4H), 3.85 (br s, 2H), 3.58–3.51 (m, 2H), 3.29–3.15 (m, 5H), 2.19–2.07 (m, 4H). After 1 hr at 25° C. the mixture was purified directly by preparative HPLC the product was collected