Sodium hydride → 5-([1S,2R,4R]-2-benzenesulfonylmethyl-4-tert-butoxycarbonyl-aminocyclohexylamino)-3-(3-trifluoromethylphenyl)pent-2-enoic acid tert-butyl ester

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A solution of compound 61j (1.45 g, 3.9 mmol) in methanol (10 mL) was stirred on an ice bath and treated dropwise over 40 min with a solution of 1-(3-trifluoromethylphenyl)propenone (see procedure 28a, 786 mg, 3.9 mmol). The mixture was stirred at room temperature for 2 h, then was concentrated under vacuum. The residue was purified by flash column chromatography, eluting with 55% ethyl acetate-hexane, to provide (1R,3R,4S)-{3-benzene-sulfonylmethyl-4-[3-oxo-3-(3-trifluoromethylphenyl)-propylamino]cyclohexyl}carbamic acid tert-butyl ester (1.16 g) as a white glassy solid. MS found: (M+H)+=569.35. (102b) A suspension of sodium hydride (60%, 176 mg, 4.4 mmol) in tetrahydrofuran (5 mL) was stirred on an ice bath and treated dropwise over 5 min with dimethylphosphonoacetic acid tert-butyl ester (0.79 mL, 4.0 mmol). The mixture was stirred at room temperature for 25 min, then was cooled on an ice bath and treated with a solution of (1R,3R,4S)-{3-benzenesulfonylmethyl-4-[3-oxo-3-(3-trifluoromethylphenyl)-propylamino]cyclohexyl}carbamic acid tert-butyl ester (1.138 g, 2.0 mmol) in tetrahydrofuran (5 mL). The mixture was stirred at room temperature for 2.5 h, then was treated with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, and the organic extracts were dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography, eluting with 25% ethyl acetate-hexane, to provide the E isomer of 5-([1S,2R,4R]-2-benzenesulfonylmethyl-4-tert-butoxycarbonyl-aminocyclohexylamino)-3-(3-trifluoromethylphenyl)pent-2-enoic acid tert-butyl ester (511 mg) as a white solid. MS found: (M+H)+=667.41. Further elution with 40% ethyl acetate-hexane provided the corresponding Z isomer (567 mg) as a white glassy solid. MS found: (M+H)+=667.41. (102c) A solution of the E isomer of 5-([1S,2R,4R]-2-benzenesulfonylmethyl-4-tert-butoxycarbonylaminocyclohexyl-amino)-3-(3-trifluoromethylphenyl)pent-2-enoic acid tert-butyl ester (495 mg) in dichloromethane (10 mL) was treated with trifluoroacetic acid (5 mL). After standing at room temperature for 4 h, the mixture was concentrated under vacuum to provide the E isomer of 5-([1S,2R,4R]-4-amino-2-benzenesulfonylmethylcyclohexylamino)-3-(3-trifluoromethyl-phenyl)pent-2-enoic acid, bis-trifluoroacetic acid salt, as a white glassy solid (736 mg) containing excess trifluoro-acetic acid. MS found: (M+H)+=511.20. Without further purification, this material was dissolved in dichloromethane (5 mL) and treated sequentially with diisopropylethylamine (0.78 mL, 4.45 mmol), 4-(N,N-dimethylamino)pyridine (91 mg, 0.74 mmol) and TBTU (262 mg, 0.82 mmol). The solution was stirred at room temperature for 17.5 h, then was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography, eluting with 4% methanol-dichloromethane containing 0.4% aqueous ammonia, and then by reverse phase HPLC. The resulting product was converted to the free base by partitioning between 1N sodium hydroxide and ethyl acetate to provide the title product (130 mg) as a white glassy foam. MS found: (M+H)+=493.37.

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