1,1'-(Diazomethylene)bis(benzene) → (S)-benzyl 2-(1-(benzhydryloxy)-3-(3,4-dihydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazine-carboxylate

A solution of benzophenone hydrazone (20.0 g, 102 mmol) in DCM (100 mL) was cooled to <0° C. and iodine (0.052 g, 0.204 mmol) and 1,1,3,3-tetramethylguanidine (25.6 mL, 204 mmol) were added. m-CPBA (30.5 g, 132 mmol) was added portion-wise between −10° C. and 0° C. over 5 minutes (exothermic, dry ice/acetone bath to control). The mixture was stirred between 0° C. and 12° C. for 15 minutes and then washed with water (3×200 mL). The resulting mixture was dried (Na2SO4), concentrated to 76 mL total volume, and rinsed into a 125 mL Erlenmeyer flask with an additional 16 mL of DCM, to make an approximately 1 M dark purple solution of (diazomethylene)dibenzene. In a separate flask, a slurry of (S)-2-(2-((benzyloxy)carbonyl)hydrazinyl)-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid compound with tetrahydrofuran (4:3) (30.7 g, 74.0 mmol) in IPA (300 mL) was cooled to less than 10° C. and the (diazomethylene)dibenzene solution (78 mL, 78 mmol) was added. The resulting mixture was warmed to room temperature and LC-MS showed a stalled reaction after 30 minutes. Additional diphenyldiazomethane (0.2 eq, 14 mL) was added and stirring continued at room temperature. After 35 minutes, the remaining diphenyldiazomethane solution (9 mL) was added. After 2 hours, 20 minutes, a purple color persisted and LC-MS showed that the reaction was complete. The reaction mixture was concentrated to approximately 60 mL and 20% aq. CH3CN (300 mL) was added. The mixture was washed with cyclohexane (10×300 mL), ethyl acetate (450 mL) added, and the mixture was washed with saturated aqueous NaHCO3 (150 mL) and brine (60 mL). The mixture was dried (Na2SO4) and concentrated, giving (S)-benzyl 2-(1-(benzhydryloxy)-3-(3,4-dihydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazine-carboxylate (39.4 g, 74.8 mmol, >99% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.65 (br s, 2H), 8.19 (br s, 1H), 7.43-7.20 (m, 15H), 6.70 (s, 1H), 6.55 (d, J=2.0 Hz, 1H), 6.45 (d, J=8.0 Hz, 1H), 6.20 (dd, J=7.9, 2.0 Hz, 1H), 4.95 (d, J=3.4 Hz, 2H), 2.81 (d, J=13.6 Hz, 1H), 2.67 (d, J=13.7 Hz, 1H), 1.17 (d, J=3.1 Hz, 3H); MS (ESI) m/z 549 [M+Na]+.

1. washwashed with water (3×200 mL)
2. dry with materialThe resulting mixture was dried (Na2SO4)
3. concentrationconcentrated to 76 mL total volume
4. washrinsed into a 125 mL Erlenmeyer flask with an additional 16 mL of DCM
5. customa stalled reaction after 30 minutes
6. stirringstirring
7. customcontinued at room temperature
8. waitAfter 35 minutes
9. waitAfter 2 hours
10. custom20 minutes
11. concentrationThe reaction mixture was concentrated to approximately 60 mL and 20% aq. CH3CN (300 mL)
12. additionwas added
13. washThe mixture was washed with cyclohexane (10×300 mL), ethyl acetate (450 mL)
14. additionadded
15. washthe mixture was washed with saturated aqueous NaHCO3 (150 mL) and brine (60 mL)
16. dry with materialThe mixture was dried (Na2SO4)
17. concentrationconcentrated

ORD record

ord-46873918805c43398221a0b28f2abc13

Source dataset

uspto-grants-2016_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09446059B2