反应详情

温度

2.5 °C

N-(5-tert-Butyl-2-methyl-4-thiocyanatophenyl)carbamic acid tert-butyl ester (31) (114 g, 356 mmol) was treated with sodium hydrosulfide hydrate (57.5 g), sodium borohydride (76.8 g), and tetrahydrofuran (1.24 L) under a nitrogen atmosphere. The mixture was stirred and cooled to 0-5° C. and a solution of water (180 mL) and methyl alcohol (300 g) added dropwise over 75 minutes at 5-10° C. The mixture was stirred at 5-15° C. for 5 hours and then at 15-25° C. for 10 hours. Water (1.25 L) and toluene (1.25 L) were added and the mixture stirred and cooled to 5° C. Glacial acetic acid (250 mL) was added slowly at 5-10° C. over 1.5 hours (caution! foaming with hydrogen gas evolution). The organic phase was separated and the aqueous phase discarded. The organic layer was washed with water (2×1.2 L) and then concentrated under vacuum to give N-(5-tert-butyl-4-mercapto-2-methylphenyl)carbamic acid tert-butyl ester (32) which was used without further purification in the next step. The N-(5-tert-butyl-4-mercapto-2-methylphenyl)carbamic acid tert-butyl ester (32) was dissolved in toluene (500 mL) and pyridine (32.0 g) added. The resulting solution was added dropwise over 3 hours and 45 minutes to a cold (8-13° C.) solution of p-toluenesulfonyl bromide (95.3 g) in ethyl acetate (750 mL). The resulting mixture was agitated at 10-15° C. for 3 hours. Water (800 mL) was added to the mixture and the organic phase separated and washed with 1N hydrochloric acid (2×500 mL) and then with water (500 mL). The organic layer was concentrated under vacuum to give 188 g crude toluene-4-thiosulfonic acid S-(4-tert-butoxycarbonylamino-2-tert-butyl-5-methylphenyl). This was treated with heptane (440 mL) and toluene (25 mL) and the resulting solution treated with S-(4-tert-butoxycarbonylamino-2-tert-butyl-5-methyl-phenyl) ester seed crystals. The mixture was stirred and cooled overnight to −5° C. The mixture was filtered and the product washed with cold heptane (2×125 mL) and vacuum dried at 40° C. to give 136 g (302 mmol, 85% yield) toluene-4-thiosulfonic acid S-(4-tert-butoxycarbonylamino-2-tert-butyl-5-methyl-phenyl) ester (33a): mp: 106-108° C.; Assay (HPLC): 99.2 area %.

1. stirringThe mixture was stirred at 5-15° C. for 5 hours
2. stirringthe mixture stirred
3. temperaturecooled to 5° C
4. customThe organic phase was separated
5. washThe organic layer was washed with water (2×1.2 L)
6. concentrationconcentrated under vacuum