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G. L. Newton et al. / Bioorg. Med. Chem. 19 (2011) 3956–3964
187.0, 162.1, 161.3, 152.8, 150.9, 147.5, 147.0, 145.1, 144.4, 143.9,
142.7, 140.1, 139.5, 41.0, 40.9; HREIMS [M+Na]+ m/z: 370.0389
(calcd for C16H13NNaO6S, 370.0361).
mide (12.79 g, 0.0622 mmol) in DMF (40 mL) was added drop wise
over 30 min. The reaction was then warmed over 2 h to 0 °C, stirred
at 0 °C for 3 h, warmed to rt over 2 h, then stirred at rt for 12 h.
Care was taken to stir vigorously and warm the reaction slowly.
The reaction was cooled to 0 °C and terminated by the addition
of 5% aq MeOH (100 mL). The mixture was then filtered with EtOAc
(800 mL) through DCVC column charged with 100 g of Celite
(packed at top of column) and 150 g of silica gel (packed at bottom
of column). The eluted material was concentrated on a rotary evap-
orator and recrystallization from toluene to afford 16.21 g (79%) of
51 as a white powder. Mp 168–171 °C, 1H NMR (500 MHz, CDCl3) d
8.00 (d, J = 1.7 Hz, 1H); 7.76 (dd, J = 1.7, 7.6 Hz, 1H); 7.73 (ddd,
J = 0.6, 1.8, 8.1 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.44 (m, 1H), 7.41
(br s, 1H), 7.35 (dddd, J = 0.6, 1.6, 5.2, 12.8 Hz, 1H), 7.32 (dddd,
J = 0.6, 1.6, 7.5, 14.8 Hz, 1H), 7.27 (m, 2H), 7.20 (m, 2H), 5.80 (d,
J = 15.2 Hz, 1H), 4.91 (d, J = 15.2 Hz, 1H), 3.89 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 169.9, 165.8, 143.5, 141.8, 138.9, 138.3,
137.7, 134.6, 133.6, 131.8, 131.7, 131.4, 131.4, 129.9, 129.2,
128.3, 127.8, 127.5, 126.8, 126.3, 54.2, 52.7; HREIMS [M+Na]+ m/
z: 432.0527 (calcd for C22H16ClNNaO3S, 432.0437).
4.2.2. Methyl 3-amino-4-((2-(methoxycarbonyl)phenyl)thio)-
benzoate (47)
PtO2 (0.3 g) and Pd on carbon (5.0 g) were suspended in a mix-
ture of compound 46 (21.42 g, 0.0669 mmol) in EtOAc (300 mL)
and MeOH (300 mL). The flask was degassed, charged with H2
and stirred under a constant atmosphere of H2 (ballon of H2). After
12 h, the reaction was complete as evident by TLC analyses. The
reaction degassed, filled with N2 and filtered through a 200 g plug
of silica gel eluting with 1:10 MeOH/EtOAc (600 mL). The elutant
was concentrated on a rotary evaporator to afford 19.12 g (98%)
of an off-white powder 47, mp 92–95 °C (dec), 1H NMR
(500 MHz, CDCl3)
d 8.19 (dd, J = 1.9, 9.8 Hz, 1H); 7.56 (d,
J = 10.0 Hz, 1H); 7.51 (d, J = 2.1 Hz, 1H), 7.42 (dd, J = 2.2, 1.0 Hz,
1H), 7.24 (m, 1H), 7.10 (dd, J = 5.1, 14.2 Hz, 1H), 6.55 (d,
J = 10.0 Hz, 1H), 3.70 (br s, 2H, NH), 3.12 (s, 3H), 3.06 (s, 3H); 13C
NMR (125 MHz, CDCl3) d 189.5, 189.4, 167.4, 156.3, 153.2, 147.1,
146.8, 145.3, 139.0, 138.3, 136.7, 130.1, 129.7, 125.9, 46.3; HREIMS
[M+H]+ m/z: 318.0870 (calcd for C16H16NO4S, 318.0800).
4.2.5. 10-(3-Chlorobenzyl)-N-(3-(cyclohexyl(methyl)amino)-
propyl)-11-oxo-10,11 dihydrodibenzo[b,f][1,4]thiazepine-8-
carboxamide (52)
4.2.3. Methyl 11-oxo-10,11-dihydrodibenzo[b,f][1,4]-thiaze-
pine-8-carboxylate (50)
Ester 51 (16.12 g, 0.0393 mol) was dissolved in THF (170 mL)
containing H2O (30 mL). After cooling to 0 °C, LiOHꢁH2O (4.95 g,
0.117 mol) was added in one portion. After 2 h at 0 °C, the reaction
was warmed to rt. HPLC or TLC indicated that hydrolysis was com-
plete after 23 h at which point the pH was adjusted to 7.0 by the
addition of 2 M HCl. The remaining mixture was dried by sequen-
tial rotary evaporation followed by lyophilization with MeOH
(6 ꢂ 100 mL) resulting in yellow wax. The wax was further dried
by rotary evaporation of toluene (3 ꢂ 120 mL). The resulting mate-
rial was suspended in EtN(iPr)2 (20.55 mL, 0.117 mmol) in DMF
(150 mL). After cooling to 0 °C, HATU (22.42 g, 0.0590 mol) was
in three portions over 15 min. The reaction was warmed to rt over
1 h. After an additional 2 h at rt, N-1-cyclohexyl-N-1-methylpro-
pane-1,3-diamine (7.00 g, 0.0411 mmol) was added in 10 mL
DMF. After 18 h of vigorous stirring at rt, the mixture was diluted
in EtOAc (200 mL) and filtered with a mixture of 1:5 MeOH/EtOAc
(1 L) through a DCVC column charged with 100 g of Celite (packed
at top of column) and 100 g of silica gel (packed at bottom of col-
umn). The elutant was concentrated on a rotary evaporator. Flash
chromatography (2:1 Hx/EtOAc to 10:1 MeOH/EtOAc) afforded
5.68 g (81%) of clear wax 52. 1H NMR (500 MHz, CD3OD) d 7.96
(d, J = 1.9 Hz, 1H), 7.65 (m, 2H); 7.56 (dd, J = 1.9, 8.1 Hz, 1H), 7.48
(m, 1H), 7.40 (m, 1H), 7.38 (m, 2H), 7.29 (dd, J = 1.5, 7.4 Hz, 1H),
7.22 (t, J = 7.6 Hz, 1H), 7.18 (m, 1H) 5.84 (d, J = 15.5 Hz, 1H), 4.95
(d, J = 15.5 Hz, 1H), 3.44 (td, J = 1.7, 6.4 Hz, 2H), 3.20 (ddt, J = 3.4,
11.9, 14.3 Hz, 2H), 3.13 (t, J = 7.5 Hz, 2H), 2.76 (s, 3H), 1.98 (m,
4H), 1.88 (m, 2H), 1.67 (m, 1H), 1.47 (dq, J = 2.8, 12.9 Hz, 2H),
1.34 (tq, J = 2.8, 12.1 Hz, 2H), 1.17 (tq, J = 3.6, 13.0 Hz, 2H 1H);
13C NMR (125 MHz, CD3OD) d 171.1, 169.1, 144.4, 141.7, 140.5,
139.7, 138.9, 137.0, 135.4, 134.6, 132.8, 132.5, 132.4, 131.1,
130.4, 129.2, 128.7, 127.5, 126.6, 126.4, 66.5, 54.6, 52.5, 38.9,
37.1, 36.6, 31.8, 27.8, 26.3, 26.2, 26.1; HREIMS [M+Na]+ m/z:
570.1917 (calcd for C31H34ClN3NaO2S, 570.1958).
Amine 47 (19.12 g, 0.0602 mol) was dissolved in THF (425 mL)
containing H2O (75 mL). The mixture was cooled to 0 °C and
LiOHꢁH2O (7.58 g, 0.181 mol) was added in one portion. After 1 h,
the reaction was warmed to rt. HPLC or TLC monitoring indicated
that hydrolysis was complete after 36 h at rt. The pH was adjusted
to 4.0 by the addition of 2 M HCl. The remaining mixture was dried
to an off white powder by rotary evaporation followed by lyophi-
lization with MeOH (6 ꢂ 300 mL). The resulting powder was fur-
ther dried by rotary evaporation with toluene (3 ꢂ 300 mL) and
suspended in DMF (400 mL). After cooling to ꢃ20 °C, 1,10-car-
bonyl-diimidazole (48.84 g, 0.301 mol) was added in portions over
3 h. The flask was equipped with a drying tube filled Drierite. The
reaction was warmed to rt over 2 h. After 24 h of vigorous stirring
at rt, reaction was cooled to 0 °C and methanol (200 mL) was
added. The reaction was warmed over 1 h to rt and stirred for an
addition 12 h. The contents of the flask were then diluted in EtOAc
(200 mL) and filtered with 1:10 MeOH/EtOAc (2 L) through a DCVC
column charged with 250 g of Celite (packed at top of column) and
500 g of silica gel (packed at bottom of column). The elutant was
concentrated on a rotary evaporator. Recrystallization from a min-
imal amount hot toluene followed by slow cooling to rt and storage
at 4 °C for 24 h provided 14.21 g (83%) of methyl ester 50 as a
white powder. The remaining mother liquor contained a mixture
of 50 and its corresponding acid 49 that could be converted to 50
(1.23 g, 6% yield) by treatment with 0.5 M TMSCH2N2 in THF. This
recycled material was not tabulated in the yield. Mp 179–181 °C,
1H NMR (500 MHz, CDCl3) d 8.48 (s, 1H, NH), 7.85 (dd, J = 1.9,
7.4 Hz, 1H); 7.79 (d, J = 1.7 Hz, 1H); 7.77 (dd, J = 1.7, 8.0 Hz, 1H),
7.63 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 1.5, 7.5 Hz, 1H), 7.40 (ddd,
J = 1.6, 8.3, 11.4 Hz, 1H), 7.39 (ddd, J = 1.6, 8.4, 8.7 Hz, 1H), 3.89
(s, 3H); 13C NMR (125 MHz, CDCl3) d 170.2. 166.3, 140.1, 137.2,
136.8, 136.0, 133.5, 133.0, 132.5, 132.5, 132.0, 129.6, 127.3,
124.2, 53.1; HREIMS [M+Na]+ m/z: 308.0489 (calcd for
C
15H11NNaO3S, 308.0357).
4.2.6. N-[3-(Cyclohexylmethylamino)propyl]-10-[(3-chloro-
phenyl)methyl]-10,11-dihydro-11-oxo-dibenzo-[b,f][1,4]-
thiazepine-8-carboxamide-5-oxide (2)
Sulfide 52 (2.25 g, 4.09 mmol) was dissolved in CH2Cl2 (200 mL)
containing NaHCO3 (1.72 g, 20.43 mmol). m-CPBA was purified by
dissolving commercial material in CH2Cl2 and washing repetitively
with a 10% w/v solution of NaHCO3, brine, and then drying by ro-
tary evaporation. A sample of freshly purified m-CPBA (0.78 g,
4.2.4. Methyl 10-(3-chlorobenzyl)-11-oxo-10,11-dihydrodi-
benzo[b,f][1,4]thiazepine-8-carboxylate (51)
NaH washed free of oil (1.49 g, 0.0622 mol) was added carefully
in portions to ester 50 (14.21, 0.0498 mol) dissolved in DMF
(200 mL) under Ar at ꢃ20 °C. After warming to 5 °C over 1 h, the
resulting suspension was cooled to ꢃ20 °C and 3-chlorobenzylbro-