2436
H. J. Breslin et al. / Bioorg. Med. Chem. 7 (1999) 2427±2436
()-7-Chloro-1,3,4,5-tetrahydro-1-methyl-4-(3-methyl-2-
butenyl)-3-(1-methylethyl)-2H-1,4-benodiazepin-2-one hy-
drochloride (1:1) (4cc). This material was prepared
following the typical procedure I to yield desired 4cc
after puri®cation as outlined in Table 2 (TLC: 20:1
Acknowledgments
We appreciate the assistance of John Masucci and Wil-
liam Jones of the R.W. Johnson Pharmaceutical Research
Institute for obtaining mass spectra data and Diane Gau-
thier of the R.W. Johnson Pharmaceutical Research
Institute for obtaining NMR data. We also thank
Hilda Azijn for technical assistance in the HIV-1 testing,
Laurene Latham for information and data retrieval, and
James Fortunato for nomenclature assistance.
1
CH2Cl2:MeOH, Rf=0.8). Free Base sample of 4cc: H
NMR (CDCl3) d 0.65±0.7 (d, 3H), 0.8±0.85 (d, 3H), 1.2±
1.3 (m, 1H), 1.7 (s, 3H), 1.75 (s, 3H), 2.9±2.95 (d, 1H),
3.05±3.15 (bdd, 1H), 3.25±3.4 (m, 5H), 3.6±3.65 (d, 1H),
5.2±5.3 (bt, 1H), 7.05±7.1 (d, 1H), 7.3±7.35 (m, 2H).
References
Procedure P
() - Ethyl N - (3 - methyl - 2 - butenyl)alanine (14). Et3N
(16.7 mL, 0.12 mol) was added to a room temperature
mixture of 1213 (12.1 g, 0.10 mol) in DCE (400 mL).
After stirring 0.2 h, ethyl pyruvate, 13 (10.95 mL, 0.10
mol) was added and the mixture was stirred an additional
0.4 h. NaHB(OAc)3 (29.67 g, 0.14 mol) was then added to
the mixture. After stirring 16 h the mixture was treated
with saturated aqueous NaHCO3. The organic layer was
separated, dried over MgSO4, ®ltered, and concentrated
under reduced pressure to give 14.95 g (81%) of desired 14
as an oil which was used without further puri®cation. 14:
1H NMR (CDCl3) d 1.25±1.35 (m, 6H), 1.65 (s, 3H), 1.75
(s, 3H), 3.05±3.15 (dd, 1H), 3.2±3.3 (dd, 1H), 3.3±3.45 (q
with broadening underneath, 2H), 4.2±4.3 (q, 2H), 5.2±5.3
(t, 1H).
1. Pauwels, R.; Andries, K.; Desmyter, J.; Schols, D.; Kukla,
M.; Breslin, H.; Raeymaekers, A.; Van Gelder, J.; Woes-
tenborghs, R.; Heykants, J.; Schellenkens, K.; Janssen, M. A.
C.; De Clercq, E.; Janssen, P. Nature 1990, 343, 470.
2. Kukla, M.; Breslin, H.; Pauwels, R.; Fedde, C.; Miranda,
M.; Scott, M.; Sherrill, R.; Raeymaekers, A.; Van Gelder, J.;
Andries, K.; Janssen, M. A. C.; De Clercq, E.; Janssen, P. J.
Med. Chem. 1991, 34, 746.
3. Kukla, M.; Breslin, H.; Diamond, C.; Grous, P.; Ho, C. Y.;
Miranda, M.; Rodgers, J.; Sherrill, R.; De Clercq, E.; Pauwels,
R.; Andries, K.; Moens, L.; Janssen, M. A. C.; Janssen, P. J.
Med. Chem. 1991, 34, 3187.
4. Breslin, H.; Kukla, M.; Ludovici, D.; Mohrbacher, R.; Ho,
W.; Miranda, M.; Rodgers, J.; Hitchens, T. K.; Leo, G.;
Gauthier, D.; Ho, C.; Scott, M.; De Clercq, E.; Pauwels, R.;
Andries, K.; Janssen, M. A. C.; Janssen, P. J. Med. Chem
1995, 38, 771.
5. Ho, W.; Kukla, M.; Breslin, H.; Ludovici, D.; Grous, P.;
Diamond, C.; Miranda, M.; Rodgers, J.; Ho, C.; De Clercq,
E.; Pauwels, R.; Andries, K.; Janssen, M. A. C.; Janssen, P. J.
Med. Chem 1995, 38, 794.
()-Ethyl N-(5-chloro-2-nitrobenzoyl)-N-(3-methyl-2-bu-
tenyl)alanine (16). A solution of 1514 (14.24 g, 65 mmol)
in CH2Cl2 (20 mL) was added to a 0ꢀC solution of 14
(12.02 g, 65 mmol) and Et3N (9.04 mL, 65 mmol) in
CH2Cl2 (200 mL). After stirring for 30 min upon comple-
tion of addition the mixture was extracted with water,
saturated aqueous NaHCO3, and brine. The organic
phase was then dried over MgSO4, ®ltered, and con-
centrated under reduced pressure to yield 17.94 g (75%) of
desired 16 which was used without further puri®cation
(TLC: 20:1 CH2Cl2: MeOH, Rf=0.8).
6. Ahgren, C.; Backro, K.; Bell, F. W.; Cantrell, A. S.; Clem-
ens, M.; Colacino, J. M.; Deeter, J. B.; Engelhardt, J. A.;
Hogberg, M.; Jaskunas, S. R.; Johansson, N. G.; Jordan, C.
L.; Kasher, J. S.; Kinnick, M. D.; Lind, P.; Lopez, C.; Morin,
J. M., Jr.; Muesing, M. A.; Noreen, R.; Oberg, B.; Paget, C. J.;
Palkowitz, J. A.; Parrish, C. A.; Pranc, P.; Rippy, M. K.;
Rydergard, C.; Sahlberg, C.; Swanson, S.; Ternansky, R. J.;
Unge, T.; Vasile, R. T.; Vrang, L.; West, S. J.; Zhang, H.;
Zhou, X. -X. Antimicrob. Agents Chemother. 1995, 39, 1329.
7. Dodd, R. H.; Liu, J. J. Heterocyclic Chem. 1995, 32, 523.
8. Townsend, L.; Swayze, E.; Peiris, S.; Kucera, L.; White, E.;
Wise, D.; Drach, J. Bioorg. Med. Chem. Lett. 1993, 3, 543.
9. Celnik, K.; Jankowske, Z. Pol. J. Chem. 1978, 52, 947.
10. Pialoux, G.; Youle, B.; DuPont, B.; Gazzard, B.; Cau-
wenbergh, G.; Stoels, P.; Davies, S.; De Saint Martin, J.;
Janssen, P. Lancet 1991, 338, 140.
11. Pauwels, R.; De Clercq, E.; Desmyter, J.; Balzarini, J.;
Goubau, P.; Herdewijn, P.; Vandeputte, M. J. Virol. Methods
1987, 16, 171.
12. Pauwels, R.; Balzarini, J.; Baba, M.; Snoeck, R.; Schols,
D.; Herdewijn, P.; Desmyter, J.; De Clercq, E. J. Virol. Meth-
ods 1988, 20, 209.
13. Elliott, R.; Montogomery, J. J. Med. Chem. 1977, 20, 116.
14. Peet, N. P.; Sunder, S. US Patent 4,419,357, Chem. Abstr.
1983, 99, 194993.
()-7-Chloro-3,4-dihydro-3-methyl-4-(3-methyl-2-buten-
yl) - 1H - 1,4 - benzodiazepin - 2,5 - dione (4i). Hydrazine
hydrate (12.1 mL, 0.245 mol) was added over 1 h to a
re¯uxing mixture of 16 (9.2 g, 0.025 mol) and RaNi (3.8
g; Fluka) in EtOH (500 mL). After stirring for 16 h at
re¯ux, the mixture was cooled, ®ltered over Dicalite,
and the resulting ®ltrate concentrated under reduced
pressure to give 7.93 g of residue. This material was
1
puri®ed as outlined in Table 2. 4i: H NMR (CDCl3) d
1.15±1.35 (bs, 1.5H), 1.5±1.6 (bs, 1.5H), 1.7±1.85 (bs,
6H), 3.95±4.1 (bd, 0.5H), 4.1±4.3 (q, 1.5H), 4.35±4.5
(bdd, 1H), 5.15±5.3 (bs, 1H), 6.9±6.95 (d, 1H), 7.4±7.45
(dd, 1H), 7.9±8.05 (bs, 1H), 8.15±8.25 (bs, 0.5H), 8.35±
8.45 (bs, 0.5H).