6922
D. Niculescu-Duvaz et al. / Tetrahedron Letters 46 (2005) 6919–6922
N-{4-[N,N-bis(20-(tert-butyldimethylsilyl-
Shahbakhti, H.; Webley, S.; Hochhauser, D.; Hilson, A.
19. Di-tert-butyl
oxy)ethyl)amino]phenoxycarbonyl}-L-glutamate (6): To a
J.; Blakey, D.; Begent, R. H. J. British J. Cancer 2002, 87,
600–607.
stirred solution of 4-N,N-bis(20-(tert-butyldimethylsilyl-
oxy)ethyl)amino-phenol 2 (13.2 g, 32 mmol) in toluene
(120 mL), phosgene (20% solution in toluene, 35 mL,
70 mmol) was added at once at room temperature. After
2 min, triethylamine (5.3 mL, 38 mmol) was added drop-
wise, and the formation of chloroformate 3 was complete
in 10 min as detected byIR spectra ( mOCOCl = 1784 cmꢀ1).
The solution was filtered and the filtrate evaporated to
afford an oil, which was dissolved in THF (80 mL) and
used directlyin the next reaction. Di- tert-butyl glutamate
hydrochloride 5 (9.77 g, 33 mmol) was dissolved in ethyl
acetate (100 mL) and extracted with aq Na2CO3 (100 mL).
The organic layer was dried (MgSO4) and evaporated. The
oilyresidue was dissolved in THF (80 mL). The solution
of chloroformate 3 in THF was poured over the solution
of di-tert-butyl glutamate 5 under stirring, at room
temperature, followed bytriethlaymine (4.9 mL, 35
mmol). After 5 min, the reaction was completed, as
14. Mayer, A.; Francis, R.; Sharma, S. K.; Sully, C.; Parker,
S.; Tolner, B.; Griffin, N.; Germain, M.; Beckett, P.;
Boxer, G.; Green, A.; Chester, K. A.; Begent, R. H. J.
British J. Cancer 2004, 91, S8.
15. Sharma, S.; Pedley, R.; Bhatia, J.; Boxer, G.; El-Emir, E.;
Qureshi, U.; Tolner, B.; Lowe, H.; Michael, N.; Minton,
N.; Begent, R.; Chester, K. Clin. Cancer Res. 2005, 11,
814–825.
16. Heaton, D. W.; Dines, S.; Dowell, R. S. High purity N-[4-
[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl]-L-glutamic
acid and hydrogen iodide salt as prodrugs for ADEPT
therapy. In PCT Int. Appl. WO 9620169, 1996.
17. 4-Benzyloxy-N,N-bis(2-(tert-butyldimethylsilyloxy)ethyl)-
aniline 12: A mixture of 4-benzyloxy-N,N-bis(2-hydroxy-
ethyl)aniline (9.6 g, 33.4 mmol), tert-butyldimethylsilyl
chloride (12.7 g, 84 mmol) and imidazole (7.8 g,
130 mmol) was dissolved in dryDMF (80 mL) and the
reaction stirred overnight, then the solvent was evapo-
rated, the residue taken in dichloromethane, the precipi-
tated imidazole hydrochloride filtered off, and the filtrate
evaporated. The residue was purified bycolumn chroma-
tography on silica (cyclohexane/ethyl acetate 4:1), to
monitored
m
byIR
(the
chloroformate
stretch
OCOCl = 1784 cmꢀ1 disappeared). The precipitate was
filtered off, the solvent evaporated and the residue purified
by column chromatography on silica (cyclohexane/ethyl
1
acetate 4:1) to afford 6 (20.45 g, 90%) as an oil. H NMR
1
afford 12 (16.4 g, 95%) as an oil. H NMR dH: ꢀ0.01 (s,
dH: 0.00 (s, 12H, 2 · SiMe2), 0.84 (s, 18H, 2 · Sit-Bu), 1.39
(s, 9H, COO-t-Bu), 1.40 (s, 9H, COO-t-Bu), 1.75–2.05
(2m, 2H, CH2CH(NH)–), 2.32 (t, 2H, CH2COO,
J = 7.69 Hz), 3.44 (t, 4H, N(CH2CH2OSi)2, J = 5.99 Hz),
3.70 (t, 4H, N(CH2CH2OSi)2, J = 5.68 Hz), 3.90–4.05 (m,
1H, CH(NH)–), 6.61 (d, 2H, Harom2+6, J = 9.18 Hz), 6.83
12H, 2 · SiMe2), 0.84 (s, 18H, 2 · Sit-Bu), 3.39 (t, 4H,
N(CH2CH2OSi)2, J = 6.01 Hz), 3.67 (t, 4H, N(CH2CH2-
OSi)2, J = 5.99 Hz), 4.96 (s, 2H, PhCH2), 6.59 (d, 2H,
Harom3+5
, J = 9.14 Hz), 6.82 (d, 2H, Harom2+6, J =
9.10 Hz), 7.25–7.44 (m, 5H, Harom benzyl). MS (FAB): 516
(M++H). Microanalysis (C29H49NO3Si2) required: C,
67.52; H, 9.57; N, 2.72; found C, 67.09; H, 9.41; N, 2.69.
18. 4-[N,N-bis(2-(tert-butyldimethylsilyloxy)ethyl)amino]phe-
nol 2: The benzyl ether 12 (11.4 g, 22.1 mmol) was
dissolved in THF, Pd/C catalyst (1.6 g) was added and
the suspension stirred overnight under H2 atmosphere.
The catalyst was filtered off, and the solvent evaporated to
afford 2 (9.4 g, 100%) as an oil. 1H NMR dH: 0.00 (s, 12H,
SiMe2), 0.84 (s, 18H, Sit-Bu), 3.34 (t, 4H, N(CH2-
CH2OSi)2, J = 6.09 Hz), 3.65 (t, 4H, N(CH2 CH2OSi)2,
J = 6.06 Hz), 6.51 (d, 2H, Harom2+6, J = 9.23 Hz), 6.58 (d,
2H, Harom3+5, J = 9.15 Hz), 8.46 (s, 1H, OH). MS (FAB):
425 (M+). Microanalysis (C22H43NO3Si2) required: C,
62.06; H, 10.18; N, 3.29; found C, 61.69; H, 9.79; N, 3.10.
(d, 2H, Harom3+5
, J = 9.03 Hz), 7.87 (d, 1H, NH,
J = 7.85 Hz).
20. Di-tert-butyl N-{4-[N,N-bis(2-hydroxyethyl)amino]phen-
oxycarbonyl}-L-glutamate (7): To solution of
a
6
(20.45 g, 28.8 mmol) in THF (315 mL) was added
Et3NÆ3HF (42 mL). The solution was stirred at room
temperature for 12 h, then the solvent was evaporated, the
residue was taken in ethyl acetate (100 mL) and extracted
with water (100 mL), aq Na2CO3 (100 mL) and water
again (100 mL). The organic layer was dried (MgSO4) and
evaporated to afford 7 (13.4 g, 97%) as a foamysolid.
All the analytical data were identical with those of
compound 7 obtained bythe procedure described bythe
works of Niculescu-Duvaz et al.5