N,N'-di(propan-2-yl)ethane-1,2-diamine

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

Procedure: Following the procedure of Example 1, m-nitrobenzenesulfonyl chloride was reacted with N,N'-diisopropyl ethylene diamine to give N-(1-methylethyl)-N-[2-[(1-methylethyl)amino]ethyl]-3-nitrobenzene sulfonamide.

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

Procedure: Following the procedure of Example 1, m-nitrobenzenesulfonyl chloride was reacted with N,N'-diisopropyl ethylene diamine to give N-(1-methylethyl)-N-[2-[(1-methylethyl)amino]ethyl]-3-nitrobenzene sulfonamide.

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

Procedure: 4-Acetaminobenzene sulfonyl chloride (23.3 g, 0.1 mole) as a slurry in 400 ml methylene chloride was added to N,N'-diisopropyl ethylene diamine (14.46 g, 0.1 mole) and triethylamine (10.1 g, 0.1 mole) in methylene chloride (600 ml). The reaction was stirred overnight at room temperature. The reaction was washed with water, insoluble by-product filtered off, and the filtrate stripped to a brown gum. After filtration through silica gel in 20% MeOH/EtOAc the crude crystalline product was recrystallized from isopropanol to provide the title product as the hydrochloride salt (3.00 g, m.r. 176°-178° C.). The reaction was washed with water, insoluble by-product filtered off After filtration through silica gel in 20% MeOH/EtOAc the crude crystalline product was recrystallized from isopropanol

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

Procedure: 4-Acetaminobenzene sulfonyl chloride (23.3 g, 0.1 mole) as a slurry in 400 ml methylene chloride was added to N,N'-diisopropyl ethylene diamine (14.46 g, 0.1 mole) and triethylamine (10.1 g, 0.1 mole) in methylene chloride (600 ml). The reaction was stirred overnight at room temperature. The reaction was washed with water, insoluble by-product filtered off, and the filtrate stripped to a brown gum. After filtration through silica gel in 20% MeOH/EtOAc the crude crystalline product was recrystallized from isopropanol to provide the title product as the hydrochloride salt (3.00 g, m.r. 176°-178° C.). The reaction was washed with water, insoluble by-product filtered off After filtration through silica gel in 20% MeOH/EtOAc the crude crystalline product was recrystallized from isopropanol

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere: 2,6-dimethylphenol (1.0 equivalent, 40 mmoles) was dissolved in dichloromethane (40 mL) and diisopropyl ethylene diamine (1.3 equivalents, 53.2 mmoles). This solution was cooled to −78° C. Chloroacetylchloride was added all at once. The reaction was followed by TLC (25 EtOAc:75 Hexanes) until reaction was complete (˜10 minutes). The reaction was extracted using water and ether. The ether layer was washed with water and then brine, dried (MgSO4), filtered, rinsed with ether, and concentrated under vacuum. The concentrate was purified by silica gel column chromatography using hexanes as eluant, to afford 10.5 grams (94.6 % yield) of chloro-acetic acid 2,6-dimethyl-phenyl ester product as a tan oil. (˜10 minutes) The reaction was extracted The ether layer was washed with water brine, dried (MgSO4) filtered rinsed with ether concentrated under vacuum The concentrate was purified by silica gel column chromatography

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere: 2,6-dimethylphenol (1.0 equivalent, 40 mmoles) was dissolved in dichloromethane (40 mL) and diisopropyl ethylene diamine (1.3 equivalents, 53.2 mmoles). This solution was cooled to −78° C. Chloroacetylchloride was added all at once. The reaction was followed by TLC (25 EtOAc:75 Hexanes) until reaction was complete (˜10 minutes). The reaction was extracted using water and ether. The ether layer was washed with water and then brine, dried (MgSO4), filtered, rinsed with ether, and concentrated under vacuum. The concentrate was purified by silica gel column chromatography using hexanes as eluant, to afford 10.5 grams (94.6 % yield) of chloro-acetic acid 2,6-dimethyl-phenyl ester product as a tan oil. (˜10 minutes) The reaction was extracted The ether layer was washed with water brine, dried (MgSO4) filtered rinsed with ether concentrated under vacuum The concentrate was purified by silica gel column chromatography

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

Procedure: p-Nitrobenzenesulfonyl chloride (22.1 g, 0.1 mole) in methylene chloride (150 ml) was added dropwise with stirring to N,N'-diisopropyl ethylene diamine (14.4 g, 0.1 mole) and triethylamine (10.1 g, 0.1 mole) in methylene chloride (400 ml). The reaction was stirred one hour at room temperature, washed with water and the solvent removed. The residue dissolved in diethyl ether precipitated the unwanted "bis" byproduct which was filtered and discarded. Chromatography of the filtrate on Dry Column Silica Gel (500 g) with ethyl acetate provided pure product free base as a gum (14.31 g). Conversion, using isopropanol/HCl, to the hydrochloride salt provided the title compound as the hydrochloride salt (14.85 g) m.r. 219°-222° C. washed with water the solvent removed The residue dissolved in diethyl ether precipitated the unwanted "bis" byproduct which was filtered Chromatography of the filtrate on Dry Column Silica Gel (500 g) with ethyl acetate provided pure product free base as a gum (14.31 g)

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

Procedure: p-Nitrobenzenesulfonyl chloride (22.1 g, 0.1 mole) in methylene chloride (150 ml) was added dropwise with stirring to N,N'-diisopropyl ethylene diamine (14.4 g, 0.1 mole) and triethylamine (10.1 g, 0.1 mole) in methylene chloride (400 ml). The reaction was stirred one hour at room temperature, washed with water and the solvent removed. The residue dissolved in diethyl ether precipitated the unwanted "bis" byproduct which was filtered and discarded. Chromatography of the filtrate on Dry Column Silica Gel (500 g) with ethyl acetate provided pure product free base as a gum (14.31 g). Conversion, using isopropanol/HCl, to the hydrochloride salt provided the title compound as the hydrochloride salt (14.85 g) m.r. 219°-222° C. washed with water the solvent removed The residue dissolved in diethyl ether precipitated the unwanted "bis" byproduct which was filtered Chromatography of the filtrate on Dry Column Silica Gel (500 g) with ethyl acetate provided pure product free base as a gum (14.31 g)

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

Procedure: Obtained as a colorless oil (41%) from tert-butyl[(2,5-difluoro-4-isocyanatobenzyl)oxy]dimethylsilane (intermediate 141; 0.43 g, 1.46 mmol), trans-4-[(2-hydroxyethyl)(methyl)amino]cyclohexylhydroxy(di-2-thienyl)acetate (intermediate 60; 0.57 g, 1.46 mmol) and diisopropylethylendiamine (0.38 mL, 2.22 mmol) following the experimental procedure as described in intermediate 61 (reaction time and temperature: 24 hours at 60° C.), followed by a purification by column chromatography with silica gel, eluting with methylene chloride/ethanol (9:1).

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

Procedure: Obtained as a colorless oil (41%) from tert-butyl[(2,5-difluoro-4-isocyanatobenzyl)oxy]dimethylsilane (intermediate 141; 0.43 g, 1.46 mmol), trans-4-[(2-hydroxyethyl)(methyl)amino]cyclohexylhydroxy(di-2-thienyl)acetate (intermediate 60; 0.57 g, 1.46 mmol) and diisopropylethylendiamine (0.38 mL, 2.22 mmol) following the experimental procedure as described in intermediate 61 (reaction time and temperature: 24 hours at 60° C.), followed by a purification by column chromatography with silica gel, eluting with methylene chloride/ethanol (9:1).

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

Procedure: Obtained as a yellow solid (14%) from 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-isocyanato-4-methoxybenzonitrile (intermediate 132; 0.48 g, 1.51 mmol), trans-4-(methylamino)cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 5, 0.44 g, 1.13 mmol) and diisopropylethylendiamine (0.6 mL, 3.44 mmol) following the experimental procedure as described in intermediate 61, followed by a purification by column chromatography with silica gel, eluting with methylen chloride/isopropanol (9:1).

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

Procedure: To a solution of trans-4-[(3-{[2-chloro-5-methoxy-4-(2-oxoethyl)phenyl]amino}-3-oxopropyl)(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 123; 173 mg, 0.16 mmol) in methanol (1.73 mL) was added (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethanaminium acetate (prepared according to preparation 8 from US20060035931) (78 mg, 0.2 mmol), diisopropylethylendiamine (0.03 mL, 0.2 mmol) and sodium triacetoxyborohydride (108 mg, 0.51 mmol). The reaction mixture was stirred for 2.5 hours at room temperature. At 0° C. the mixture was added into a 20 mL of bicarbonate 4%, then the crude was extracted with ethyl acetate, washed with water and brine, dried and the solvent was removed under reduced pressure. The crude obtained was purified by column chromatography with silica gel, eluting with methylen chloride/methanol (9:1) to give the title compound as a yellow solid (52%). the crude was extracted with ethyl acetate washed with water and brine dried the solvent was removed under reduced pressure The crude obtained was purified by column chromatography with silica gel eluting with methylen chloride/methanol (9:1)