Water-Soluble Analogues of CB30865
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 17 3701
2-yn yl)a m in o]-N-(3-p yr id ylm eth yl)ben za m id e (5a ). A so-
lution of 4a (0.094 g, 0.17 mmol) in CH2Cl2 (1.2 mL) and TFA
(1.6 mL) was stirred at room temperature for 55 min. The TFA
was then removed in vacuo, and the residue was treated with
CH2Cl2/toluene and concentrated in vacuo to leave a white
solid which dried in vacuo over P2O5 (0.142 g). This solid was
dissolved in anhydrous DMF (1.3 mL) under argon. The
reaction mixture was placed in an ice bath, and then a solution
of 3-(aminomethyl)pyridine (0.028 g, 0.255 mmol) in anhydrous
DMF (0.2 mL) was added followed by PyBOP (0.093 g, 0.178
mmol) and, finally, diisopropylethylamine (0.154 g, 1.19 mmol).
The reaction mixture was stirred at 0 °C for 3 min; the ice
bath was then removed, and stirring was continued under
argon for 3 h. The clear solution was then partitioned between
AcOEt (120 mL) and saturated aqueous NaHCO3 (60 mL). The
organic layer was washed with more saturated aqueous
NaHCO3 (50 mL) and brine (40 mL), dried (Na2SO4), and
concentrated in vacuo. Purification by column chromatogra-
phy, on gradient elution with MeOH in CH2Cl2 (5-13%),
afforded a glass. Reprecipitation from CH2Cl2/hexanes afforded
a white solid which was collected by filtration, washed with
hexanes, and dried in vacuo over P2O5 (0.070 g, 70%): mp 120
°C (softens); 1H NMR (DMSO-d6) 2.15 (s, 3H, N-Me pipera-
zine), 2.23 (br s) and 2.49 (br s obscured, 8H, N(CH2CH2)2N-
Me), 3.17 (s, poorly resolved triplet; 1H, CtCH), 3.60 (s,
3H, N3-Me), 3.61 (s, 2H, 2-CH2), 4.36 (d, J ) 1.72 Hz, 2H,
CH2CtC), 4.45 (d, J ) 5.8 Hz, 2H, CONHCH2), 4.77 (s, 2H,
6-CH2), 6.78 (d, J ) 8.9 Hz, 2H, 3,5′-ArH), 7.31 (dd, J ) 4.8,
7.8 Hz, 1H, pyr 5-H), 7.68 (d, J ) 7.8 Hz, pyr 4-H), 7.75 (d, J
) 8.8 Hz, 2H, 2′,6′-ArH), 7.80, 7.92 (2 × s, 2H, 5-H, 8-H), 8.42
(d, J ) 4.9 Hz, pyr 6-H), 8.52 (d, J ) 1.6 Hz, 1H, 2-H pyr),
8.72 (t, J ) 5.82 Hz, 1H, CONH); MS (FAB, m/z) 584 and 586
[(M + H)+; 100 and 36%, respectively; Cl isotopic pattern].
Anal. (C32H34ClN7O2‚1.2H2O) C, H, N, Cl.
mixture was stirred at room temperature for 2 h, and then
the THF was removed in vacuo. The residue was suspended
in H2O (10 mL), and the pH was adjusted to ∼5 with 1 N HCl.
The white precipitate was collected by filtration and dried in
vacuo, and then it was reprecipitated from CH2Cl2/hexanes to
afford the title compound 26 as a white solid (0.044 g, 70%):
1
mp 185-187 °C; H NMR (DMSO-d6) 1.49 (s, 9H, But), 3.25
(s, 1H, CtCH), 4.35, 4.38 (2 × s, 4H, CH2CtC and 2-CH2),
4.78 (s, 2H, 6-CH2), 5.62 (br s, 1H, OH), 6.78 (d, J ) 8.7 Hz,
2H, 3′,5′-ArH), 7.73 (d, J ) 8.6 Hz, 2H, 2′,6′-ArH), 7.78, 7.84
(2 × s, 2H, 5-H, 8-H), 12.07 (s, 1H, N3-H); FAB-HRMS
measured 453.1463, calcd for C24H24ClN3O4 453.1455. Anal.
(C24H24ClN3O4‚0.25H2O) C, H, N.
ter t-Bu tyl 4-[N-[7-Ch lor o-2-m eth a n esu lfon yloxym eth -
yl-4-oxo-3,4-d ih yd r oq u in a zolin -6-ylm et h yl]-N-(p r op -2-
yn yl)a m in o]ben zoa te (27). To a solution of 26 (0.250 g, 0.55
mmol) in anhydrous DMF (6 mL) under argon was added
methanesulfonic anhydride (0.191 g, 1.10 mmol) followed
immediately by Et3N (0.27 mL, 1.93 mmol). The clear solution
was stirred at room temperature for 45 min, and then it was
partitioned between AcOEt (200 mL) and saturated aqueous
NaHCO3 (60 mL). The organic layer was washed with more
saturated aqueous NaHCO3 (60 mL) and brine (60 mL), dried
(Na2SO4), and concentrated in vacuo. Purification by column
chromatography, on elution with 40% AcOEt in CH2Cl2,
afforded a white solid (0.212 g, 73%): mp 178-181 °C; 1H NMR
(DMSO-d6) 1.49 (s, 9H, CO2But), 3.23 (s, 1H, CtCH), 3.20 (s,
3H, SO2Me), 4.39 (s, 2H, CH2CtC), 4.78 (s, 2H, 6-CH2), 5.11
(s, 2H, 2-CH2), 6.78 (d, J ) 9.0 Hz, 2H, 3′,5′-ArH), 7.72 (d, J )
8.8 Hz, 2H, 2′,6′-ArH), 7.85, 7.88 (2 × s, 2H, 5-H, 8-H); MS
(ESI, m/z) 554 and 556 [(M + Na)+; 100 and 38%, respectively;
Cl isotopic pattern]. Anal. (C25H26ClN3O6S) C, H, N.
ter t-Bu t yl 4-[N-[7-Ch lor o-2-(p ip er id in -1-yl)m et h yl-4-
oxo-3,4-d ih yd r oqu in a zolin -6-ylm eth yl]-N-(p r op -2-yn yl)-
a m in o]ben zoa te (28). To a solution of 27 (0.201 g, 0.38 mmol)
in anhydrous DMF (5 mL) was added piperidine (0.323 g, 3.8
mmol), and the clear solution was stirred at room temperature
for 2.5 h. The reaction mixture was then partitioned between
AcOEt (200 mL) and 5% aqueous Na2CO3 (70 mL). The organic
layer was washed with 5% aqueous Na2CO3 (70 mL) and brine
(100 mL), dried (Na2SO4), and concentrated in vacuo. Puri-
fication by column chromatography, on elution with AcOEt/
CH2Cl2 (v/v, 1/1), afforded a white solid (0.179 g, 91%): mp
208-210 °C; 1H NMR (DMSO-d6) 1.36 (m), 1.48 (m, obscured),
1.49 (s, 15H, But and piperidine CH2CH2CH2), 2.42, (br s, 4H,
piperidine CH2NCH2), 3.61 (s, 2H, 2-CH2), 3.22 (s, 1H, CtCH),
4.38 (s, 2H, CH2CtC), 4.77 (s, 2H, 6-CH2), 6.77 (d, J ) 9.0
Hz, 2H, 3′,5′-ArH), 7.72 (d, J ) 8.9 Hz, 2′,6′-ArH), 7.79, 7.83
(2 × s, 2H, 5-H, 8-H), 11.96 (s, 1H, N3-H); MS (ESI, m/z) 521
and 523 [(M + H)+; 100 and 35%, respectively; Cl isotopic
pattern]. Anal. (C29H33ClN4O3) C, H, N, Cl.
2-Acet oxym et h yl-6-b r om om et h yl-7-ch lor o-3,4-d ih y-
d r oqu in a zolin -4-on e (24). To a suspension of 13 (2.00 g, 7.5
mmol) in anhydrous CCl4 (120 mL) was added NBS (1.47 g,
8.3 mmol) followed by dibenzoyl peroxide (7.0 mg) under argon.
The reaction mixture was placed in a preheated oil bath at
120 °C and was stirred at this temperature for 3.5 h while
being illuminated. The solvent was removed in vacuo, and the
residue was purified twice by column chromatography using
40% AcOEt in CHCl3 as eluant (1.02 g, 40%): mp 190-195
1
°C; H NMR (DMSO-d6) 2.14 (s, 3H, CH3CO), 4.91, 4.97 (2 ×
s, 4H, 2-CH2 and 6-CH2), 7.78 (s, 1H, 8-H), 8.36 (s, 1H, 5-H),
12.61 (s, 1H, N3-H). This product was used in the next
experiment without any further purification.
ter t-Bu t yl 4-[N-[2-Acet oxym et h yl-7-ch lor o-4-oxo-3,4-
d ih yd r oq u in a zolin -6-ylm et h yl]-N-(p r op -2-yn yl)a m in o]-
ben zoa te (25). To a stirred solution of 24 (1.02 g, 3.0 mmol)
in anhydrous DMF (100 mL) was added tert-butyl 4-N-(prop-
2-ynyl)aminobenzoate (0.78 g, 3.4 mmol) followed by 2,6-
lutidine (1.23 mL, 10.6 mmol). The reaction mixture was
placed in a preheated oil bath at 120 °C and stirred at this
temperature for 16 h under argon; it was then allowed to cool
to room temperature. The solvent was removed in vacuo, and
the residue was partitioned between AcOEt (300 mL) and half-
saturated brine (300 mL). The aqueous layer was extracted
with more AcOEt (2 × 100 mL); the combined organic extracts
were washed with brine (100 mL), dried (MgSO4), and con-
centrated in vacuo. Purification by column chromatography,
on elution with 30% AcOEt in CHCl3, afforded a white solid
(0.713 g, 48%): mp 219-220 °C; 1H NMR (DMSO-d6) 1.49 (s,
9H, But), 2.12 (s, 3H, CH3CO), 3.25 (s, 1H, CtCH), 4.40 (s,
2H, CH2CtC), 4.78 (s, 2H, 6-CH2), 4.94 (s, 2H, 2-CH2), 6.78
(d, J ) 8.8 Hz, 2H, 3′,5′-ArH), 7.72 (d, J ) 8.8 Hz, 2H, 2′,6′-
ArH), 7.81, 7.83 (2 × s, 5-H, 8-H), 12.52 (s, 1H, N3-H); FAB-
HRMS measured 495.1551, calcd for C26H26N3ClO5 495.1561.
Anal. (C26H26ClN3O5) C, H, N.
ter t-Bu tyl 4-[N-[7-Ch lor o-3-m eth oxyca r bon ylm eth yl-
4-oxo-2-p ip er id in -1-ylm eth yl-3,4-d ih yd r oqu in a zolin -6-yl-
m eth yl]-N-(p r op -2-yn yl)a m in o]ben zoa te (29a ). To a solu-
tion of 28 (0.096 g, 0.18 mmol) in anhydrous DMF (5 mL)
under argon was added NaH (60% dispersion in mineral oil, 8
mg, 0.2 mmol) in one portion. The reaction mixture was stirred
at room temperature for 3 min, and then methyl bromoacetate
(0.141 g, 0.9 mmol) was added dropwise. The reaction mixture
was stirred at room temperature for 24 h, and then partitioned
between AcOEt (150 mL) and half-saturated brine (100 mL).
The organic layer was washed with more brine (100 mL). The
combined aqueous washings were extracted with AcOEt (2 ×
50 mL). The combined AcOEt extracts were washed with brine
(100 mL), dried (Na2SO4), and concentrated in vacuo. Purifica-
tion by column chromatography, on elution with CHCl3,
afforded a white solid (0.071 g, 67%): mp 148-150 °C; 1H NMR
(DMSO-d6) 1.36 (m, 6H, piperidine CH2CH2CH2), 1.50 (s, 9H,
But), 2.32 (m, 4H, piperidine CH2NCH2), 3.23 (s, 1H, CtCH),
3.58 (s, 2H, 2-CH2), 3.67 (s, 3H, CO2Me), 4.40 (d, J ) 2.0 Hz,
2H, CH2CtC), 4.80 (s, 2H, 6-CH2), 4.87 (s, 2H, N3-CH2), 6.77
(d, J ) 9.0 Hz, 2H, 3′,5′-ArH), 7.72 (d, J ) 8.9 Hz, 2′,6′-ArH),
7.86, 7.87 (2 × s, 2H, 5-H, 8-H); MS (FAB, m/z) 593 and 595
ter t-Bu tyl 4-[N-[7-Ch lor o-2-h yd r oxym eth yl-4-oxo-3,4-
d ih yd r oqu in a zolin -6-ylm et h yl]-N-(p r op -2-yn yl)a m in o]-
ben zoa te (26). To a solution of 25 (0.070 g, 0.14 mmol) in
THF (2.7 mL) was added dropwise aqueous NaOH (1 N, 0.27
mL, 0.27 mmol) followed by H2O (0.2 mL). The reaction