Ammonia → HCID 15408476, compound

A solution of N,N′-bis(2-mercapto-2-methylpropyl)ethylenediamine (11.23 g, 47.5 mmol; see, DiZio et al., 1991, Bioconjugate Chem 2: 353 and Corbin et al., 1976, J. Org. Chem. 41: 489) in methanol (500 mL) was cooled in ice/water bath and then saturated with gaseous ammonia over 45 min. To this was added 4-methoxybenzyl chloride (17.0 mL, 125 mmol, 264 mol %). The reaction was allowed to warm to room temperature overnight with stirring under argon. The solution was concentrated to a paste and then partitioned between diethyl ether (150 mL) and 0.5 M KOH (200 mL). The aqueous layer was further extracted with diethyl ether (2×50 mL). The combined organic layers were washed with NaCl solution and concentrated to a clear colorless oil. The oil dissolved in diethyl ether (200 mL) and then acidified with 4.0 M HCl in dioxane until no further precipitation was seen. The white precipitate was collected by filtration and washed with diethyl ether. The white solid was recrystallized from hot water at a pH of ˜2. The product was collected by filtration to afford 29.94 g as a mix of mono- and di-HCl salts. The HCI salts were partitioned between 1 M KOH (100 mL) and ethyl acetate (100 nmL). The aqueous was extracted with ethyl acetate (2×30 mL) and the combined organic layers were washed with NaCl solution, dried with Na2SO4 and concentrated to give pure product as the free base as a light yellow oil (18.53 g, 82% yield). Nuclear magnetic resonance characterization experiments yielded the following molecular signature:

1. concentrationThe solution was concentrated to a paste
2. custompartitioned between diethyl ether (150 mL) and 0.5 M KOH (200 mL)
3. extractionThe aqueous layer was further extracted with diethyl ether (2×50 mL)
4. washThe combined organic layers were washed with NaCl solution
5. concentrationconcentrated to a clear colorless oil
6. dissolutionThe oil dissolved in diethyl ether (200 mL)
7. customacidified with 4.0 M HCl in dioxane until no further precipitation
8. filtrationThe white precipitate was collected by filtration
9. washwashed with diethyl ether
10. customThe white solid was recrystallized from hot water at a pH of ˜2
11. filtrationThe product was collected by filtration
12. customto afford 29.94 g as
13. customThe HCI salts were partitioned between 1 M KOH (100 mL) and ethyl acetate (100 nmL)
14. extractionThe aqueous was extracted with ethyl acetate (2×30 mL)
15. washthe combined organic layers were washed with NaCl solution
16. dry with materialdried with Na2SO4
17. concentrationconcentrated

ORD record

ord-61fb13ad28984c6f9535c1b14a656ef0

Source dataset

uspto-grants-2001_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06248304B1