N,N,N',N'-tetramethylpropane-1,3-diamine

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: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxa mide (381 mg) was suspended in acetonitrile and N,N,N′,N′-tetramethyl-1,3-propanediamine (34.0 μL) and triethylamine (0.98 mL) were added to the suspension. While this mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added dropwise. The mixture was stirred at the same temperature for 1 hour and trifluoroacetic anhydride (0.34 mL) was added dropwise, followed by stirring for another 1 hour. Subsequently, water (10 mL) was added to the reaction mixture and acetonitrile was evaporated under reduced pressure. The resulting crystal was collected by filtration, washed successively with water and diethyl ether, and dried under reduced pressure to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carbonitrile as a white crystal (567 mg, 91% yield). This compound was identical to the compound obtained in Example 3. While this mixture was cooled in a salt-ice bath by stirring for another 1 hour was evaporated under reduced pressure The resulting crystal was collected by filtration washed successively with water and diethyl ether dried under reduced pressure

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

Procedure: (2S)-4,4-difluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carbox amide (1.66 g) was suspended in acetonitrile (40 mL). To this suspension, N,N,N′,N′-tetramethyl-1,3-propanediamine (133 μL) and triethylamine (2.20 mL) were added. While the mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (1.20 mL) was added dropwise. The reaction mixture was then stirred at the same temperature for 1 hour, followed by the addition of saturated brine (20 mL) and extraction with ethyl acetate (2×80 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the resulting residue, a mixture of ethyl acetate and methanol (20:1, 30 mL) was added and the resulting crystal was collected by filtration to give (2S)-1-[2-(benzenesulfonyloxy)acetyl]-4,4-difluoropyrrolidine-2-carboxamide as a white crystal (1.60 g). The filtrate was concentrated under reduced pressure and the residue was purified on a silica gel column (ethyl acetate:methanol=20:1) to give additional (2S)-1-[2-(benzenesulfonyloxy)acetyl]-4,4-difluoropyrrolidine-2-carboxamide (0.58 g). The total amount of the product was 2.18 g (79% yield). While the mixture was cooled in a salt-ice bath dried over anhydrous sodium sulfate concentrated under reduced pressure To the resulting residue, a mixture of ethyl acetate and methanol (20:1, 30 mL) was added the resulting crystal was collected by filtration

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

Procedure: Process A: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (381 mg) and trimethylamine hydrochloride (191 mg) were suspended in acetonitrile (10 mL) and triethylamine (0.56 mL) was added to the suspension. While this mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added drop wise. The mixture was stirred for 1 hour at the same temperature, after which water (5 mL) was added and the mixture was extracted with ethyl acetate (2×40 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1) to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a white solid (528 mg, 80% yield). Process B: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (381 mg) was suspended in acetonitrile (10 mL). To this suspension, N,N,N′,N′-tetramethyl-1,3-propanediamine (34.0 μL) and triethylamine (0.56 mL) were added. While the mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added dropwise. The mixture was then stirred at the same temperature for 1 hour, followed by the addition of saturated brine (5 mL) and extraction with ethyl acetate (2×40 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1) to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a white solid (599 mg, 91% yield). Process C: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (100 mg) and triethylamine (74 mg) were suspended in acetonitrile (1 mL). While the suspension was cooled in an ice bath, benzenesulfonic anhydride (188 mg) was added and the mixture was stirred for 10 minutes. Subsequently, the mixture was stirred at room temperature for 1 hour, followed by the addition of water (2 mL) and extraction with ethyl acetate (2×4 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a brown oil (147 mg, 85% yield). While the mixture was cooled in a salt-ice bath dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1)

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

Procedure: Process A: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (381 mg) and trimethylamine hydrochloride (191 mg) were suspended in acetonitrile (10 mL) and triethylamine (0.56 mL) was added to the suspension. While this mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added drop wise. The mixture was stirred for 1 hour at the same temperature, after which water (5 mL) was added and the mixture was extracted with ethyl acetate (2×40 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1) to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a white solid (528 mg, 80% yield). Process B: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (381 mg) was suspended in acetonitrile (10 mL). To this suspension, N,N,N′,N′-tetramethyl-1,3-propanediamine (34.0 μL) and triethylamine (0.56 mL) were added. While the mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added dropwise. The mixture was then stirred at the same temperature for 1 hour, followed by the addition of saturated brine (5 mL) and extraction with ethyl acetate (2×40 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1) to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a white solid (599 mg, 91% yield). Process C: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (100 mg) and triethylamine (74 mg) were suspended in acetonitrile (1 mL). While the suspension was cooled in an ice bath, benzenesulfonic anhydride (188 mg) was added and the mixture was stirred for 10 minutes. Subsequently, the mixture was stirred at room temperature for 1 hour, followed by the addition of water (2 mL) and extraction with ethyl acetate (2×4 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a brown oil (147 mg, 85% yield). While the mixture was cooled in a salt-ice bath dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1)

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N,N′,N′-Tetramethyl-1,3-propanediamine (56.7 g) was added dropwise to a suspension of the product from step (ii) (85.0 g) and 2,4,6-trimethylbenzenesulfonyl chloride (87.8 g) in THF (452.9 g), and the mixture was heated at 45° C. for 7 hours. 2.5% HCl in water (1291 g) was added to the mixture, and the mixture was stirred at 5° C. for 30 minutes. The resulting precipitate was collected by filtration, washed with acetonitrile (2×68.0 g), and dried to give the crude subtitle compound as a solid. A stirred suspension of the solid in acetonitrile (654.5 g) was heated at 70° C. for 30 minutes, cooled to 5° C. and stirred at 5° C. for 30 minutes. The resulting precipitate was collected by filtration, washed with acetonitrile (2×68.0 g) and dried to give the subtitle compound as a solid, 113.1 g; 1H NMR CDCl3: δ 7.24 (d, 2H), 7.11 (d, 2H), 6.96 (s, 2H), 4.71 (s, 2H), 3.90 (s, 2H), 3.71 (s, 2H), 2.59 (s, 6H), 2.32 (s, 3H), 2.27 (s, 3H). The resulting precipitate was collected by filtration washed with acetonitrile (2×68.0 g) dried to give the crude subtitle compound as a solid was heated at 70° C. for 30 minutes cooled to 5° C. stirred at 5° C. for 30 minutes The resulting precipitate was collected by filtration washed with acetonitrile (2×68.0 g) dried

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: 2-Mesitylenesulfonyl chloride (4.96 g, 22.7 mmol) was added to a solution of N,N,N′,N′-tetramethyl-1,3-propanediamine (3.79 mL, 22.7 mmol) and the product of example 8 step (v) (6.55 g, 15.1 mmol) in THF (66 mL) and the mixture was stirred at RT for 3 h. The resulting mixture was diluted with water and extracted with EtOAc. And the combined organic solutions were washed with brine, dried and concentrated. The residue was purified via chromatography on silica to give 8.87 g of the subtitle compound as a white solid; 1H NMR (CDCl3); 6.93 (2H, s), 6.71 (1H, d), 6.41 (1H, d), 6.33 (1H, dd), 4.66 (2H, br s), 4.02 (2H, t), 3.78 (3H, s), 3.77-3.82 (2H, m), 3.75 (2H, s), 2.59 (6H, s), 2.31 (3H, s), 2.25 (3H, s), 1.93-2.01 (2H, m), 0.89 (9H, s), 0.05 (6H, s); LC-MS: m/z 616. extracted with EtOAc And the combined organic solutions were washed with brine dried concentrated The residue was purified via chromatography on silica

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

Procedure: To a solution of 3 g of 2-[1-(2-ethoxyethyl)-l-benzimidazol-2-yl)]-1,3-bis-dimethylaminopropane dihydrochloride in 10 ml of water is added, at 0°-15° C. and under stirring, a molar excess of a saturated solution of sodium bicarbonate. After the development of the carbon dioxide is over, the mixture is repeatedly extracted with ethyl ether (2×8, 1×4 ml). The organic phases are collected together, washed with 4 ml of a saturated solution of sodium chloride, made anhydrous on sodium sulphate and evaporated to dryness under vacuum to obtain 2.1 g of 2-[1-(2-ethoxyethyl)benzimidazol-2-yl)]-1,3-bis-dimethylaminopropane as an oil. IR (film): 3390 (broad), 2775, 2825, 2855, 2950, 2975, 1618, 1505 cm-1. is repeatedly extracted with ethyl ether (2×8, 1×4 ml) The organic phases are collected together washed with 4 ml of a saturated solution of sodium chloride evaporated to dryness under vacuum

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 1-(4-bromo-2-methylphenyl)-2-methylpropan-1-ol (600 mg), N,N,N′,N′-tetramethyl-1,3-propanediamine (0.492 mL) and toluene (0.823 mL) was added methanesulfonyl chloride (0.229 mL), and the mixture was stirred at 60° C. for 2 hr. To the reaction mixture were added methyl 4-aminobenzoate (560 mg) and N,N-diisopropylethylamine (0.862 mL) at room temperature, and the mixture was stirred at 100° C. overnight under a nitrogen atmosphere. To the reaction mixture was added water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (457.4 mg). the mixture was stirred at 100° C. overnight under a nitrogen atmosphere the mixture was extracted with ethyl acetate The extract was washed with water and saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure the residue was purified by silica gel column chromatography (ethyl acetate/hexane)