5636 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 15
Hamada et al.
1.27 (8H, m). 13C NMR (DMSO-d6, 125 MHz, δ, ppm) 172.92,
172.52, 56.35, 43.38, 41.83, 31.57, 31.49, 28.53, 28.48, 28.24,
25.74, 23.94, 23.45. MS (FAB) m/z 289 (MHþ - HCl). HRMS
calcd for C14H29N2O4, 289.2126; found, 289.2127. HPLC tR=
20.96 min (gradient (I), purity 95.0%).
of 47 (2.03 g, 11.6 mmol), benzylhydroxylamine (2.27 g, 18.4
mmol), EDCI (4.89 g, 25.5 mmol), and HOBt H2O (3.75 g, 24.5
3
mmol) in DMF (50 mL) was stirred at room temperature for 16 h.
The reaction mixture was poured into water and extracted with
AcOEt. The organic layer was washed with brine and dried over
Na2SO4. Filtration, concentration in vacuo, and purification by
silica gel flash column chromatography (AcOEt/n-hexane = 1/3)
gave 1.27 g (39%) of 48 as a colorless oil. 1H NMR (CDCl3, 500
MHz, δ, ppm) 8.41 (1H, broad s), 7.39 (5H, m), 4.90 (2H, s), 2.58
(2H, m), 2.17 (2H, m), 1.44 (9H, s).
Step 2: Preparation of tert-Butyl 4-[(benzyloxy)(8-bromooctyl)-
amino]-4-oxobutanoate (49). A mixture of 48 (640 mg, 2.29 mmol)
obtained above and 60% NaH in oil (180 mg, 4.50 mmol) in DMF
(30 mL) was stirred at room temperature for 30 min. To the mixture
was added dropwise 1,4-dibromooctane (2.14 g, 7.50 mmol), and the
mixture was stirred at 50 ꢀC for 3 h. Then, the reaction mixture was
poured into water and extracted with AcOEt. The organic layer was
washed with brine and dried over Na2SO4. Filtration, concentration
in vacuo, and purification by silica gel flash column chromatogra-
phy (AcOEt/n-hexane = 1/5) gave 455 mg (42%) of 49 as a colorless
oil. 1H NMR (CDCl3, 600 MHz, δ, ppm) 7.39 (5H, m), 4.86 (2H, s),
3.62 (2H, m), 3.39 (2H, t, J=6.6 Hz), 2.70 (2H, m), 2.54 (2H, t, J=
7.2 Hz), 1.83 (2H, quintet, J=7.8 Hz), 1.62(2H, quintet, J=6.6 Hz),
1.45 (9H, s), 1.40 (2H, quintet, J=7.2 Hz), 1.29 (6H, m).
3-{[10-(Dimethylamino)decanoyl](hydroxy)amino}propanoic
Acid Hydrochloride (9 HCl). Yield 46%; a colorless amorphous
3
solid. 1H NMR (DMSO-d6, 150 MHz, δ, ppm) 9.66 (1H, broad s),
9.19 (1H, broad s), 3.70 (2H, t, J = 7.2 Hz), 3.01 (2H, m), 2.76 (6H,
d, J =4.8Hz), 2.44 (2H, m), 2.32 (2H, t, J = 7.2 Hz), 1.58 (2H, m),
1.47 (2H, m), 1.26 (10H, m). 13C NMR (DMSO-d6, 600 MHz, δ,
ppm) 174.38, 172.52, 56.53, 43.38, 42.03, 33.55, 31.56, 31.47, 28.63,
28.53, 25.68, 24.37, 23.99, 23.55. MS (FAB) m/z 303 (MHþ
-
HCl). HRMS calcd for C15H31N2O4, 303.2281; found, 303.2284.
HPLC tR = 15.11 min (gradient (II), purity 96.5%).
3-{[11-(Dimethylamino)undecanoyl](hydroxy)amino}propanoic
Acid Hydrochloride (10 HCl). Yield 87%; a yellow amorphous
3
solid. 1H NMR (DMSO-d6, 150 MHz, δ, ppm) 9.65 (1H, broad s),
9.23 (1H, broad s), 3.70 (2H, t, J = 7.2 Hz), 3.01 (2H, m), 2.75 (6H,
d, J = 4.8 Hz), 2.44 (2H, m), 2.31 (2H, t, J = 7.2 Hz), 1.58 (2H, m),
1.47 (2H, m), 1.26 (12H, m). 13C NMR (DMSO-d6, 125 MHz, δ,
ppm) 173.15, 172.68, 56.67, 42.15, 42.12, 31.71, 31.62, 28.77, 28.48,
25.83, 24.13, 23.66. MS (FAB) m/z 317 (MHþ - HCl). HRMS
calcd for C16H33N2O4, 317.2435; found, 317.2440. HPLC tR
=
Steps 3, 4, and 5: Preparation of 4-[(8-Dimethylaminooctyl)-
(hydroxyl)amino]-4-oxobutanoic Acid Hydrochloride (13 HCl).
Compound 13 HCl was prepared from 49 obtained above using
16.03 min (gradient (II), purity 95.0%).
3-{[12-(Dimethylamino)dodecanoyl](hydroxy)amino}propanoic
3
Acid Hydrochloride (11 HCl). Yield 7.9%; a yellow amorphous
3
3
solid. 1H NMR (DMSO-d6, 600 MHz, δ, ppm) 9.65 (1H, broad
s), 9.17 (1H, broad s), 3.70 (2H, t, J = 7.2 Hz), 3.01 (2H, m), 2.75
(6H, d, J = 5.4 Hz), 2.44 (2H, m), 2.31 (2H, t, J = 7.2 Hz), 1.58
(2H, quintet, J = 6.6 Hz), 1.46 (2H, m), 1.25 (14H, m). 13C
NMR (DMSO-d6, 125 MHz, δ, ppm) 175.18, 174.12, 59.21,
45.14, 43.45, 33.32, 32.63, 32.44, 30.53, 30.12, 27.46, 27.39,
25.85, 25.70, 25.65. MS (FAB) m/z 331 (MHþ - HCl). HRMS
the procedure described for 5 (step 2) and 4 (steps 3 and 4) in 14%
yield as a colorless oil. 1H NMR (DMSO-d6, 600 MHz, δ, ppm)
9.61 (1H, broad s), 9.18 (1H, broad s), 3.47 (2H, t, J = 7.2 Hz), 3.01
(2H, m), 2.76 (6H, d, J = 5.4 Hz), 2.58 (2H, t, J = 7.2 Hz), 2.39
(2H, t, J = 7.2 Hz), 1.58 (2H, m), 1.51 (2H, quin, J = 6.6 Hz), 1.28
(8H, m). 13C NMR (DMSO-d6, 150 MHz, δ, ppm) 173.83, 56.55,
42.08, 28.22, 26.94, 26.08, 25.78, 25.57, 23.51. MS (FAB) m/z 289
(MHþ - HCl). HRMS calcd for C13H29N2O4, 289.2125; found,
289.2127. HPLC tR = 13.32 min (gradient (II), purity 99.3%).
3-({9-[Butyl(methyl)]amino}nonanoyl(hydroxy)amino)propanoic
calcd for C17H35N2O4, 331.2600; found, 331.2597. HPLC tR
=
23.49 min (gradient (II), purity 97.2%).
3-(N-Hydroxy-7-methyloctanamido)propanoic Acid (12). Steps
1 and 2: Preparation of tert-Butyl 3-[Benzyloxy(7-methylocta-
noyl)amino]propanoate (45). To a solution of 7-methyloctanoic acid
(44, 870 mg, 5.50 mmol) and oxalyl chloride (2.34 g, 18.4 mmol) in 8
mL of CH2Cl2 was added a catalytic amount of DMF. The mixture
was stirred at room temperature for 45 min. Concentration in vacuo
of the mixture gave the acid chloride of 44 as a colorless oil.
To a solution of 20 (1.81 g, 7.20 mmol), triethylamine (2 mL), and
catalytic amount of DMAP in 25 mL of CH2Cl2 was added a
solution of the acid chloride obtained above in 5 mL of CH2Cl2 in a
dropwise fashion. The mixture was stirred at room temperature for 1
h. The reaction mixture was poured into water and extracted with
AcOEt. The organic layer was separated and washed with 4N aque-
ous HCl and brine, and dried over Na2SO4. Filtration, concentartion
in vacuo, and purification by silica gel flash column chromatography
(AcOEt/n-hexane=1/10) gave 1.36 g (63%) of 45 as a colorless oil.
1HNMR(CDCl3, 500 MHz, δ,ppm) 7.38(5H,m),4.82(2H,s),3.91
(2H, t, J=5.8 Hz), 2.53 (2H, t, J = 7.0 Hz), 2.35 (2H, t, J=7.9 Hz),
1.56 (3H, t, J=7.6Hz),1.52(1H,septet,J=6.7Hz),1.41(9H,s),1.27
(4H, m), 1.15 (2H, m), 0.85 (2H, d, J=6.4 Hz).
Acid Hydrochloride (14 HCl). Compound 14 was prepared from
3
26 and butylmethylamine using the procedure described for 5 in
58% yield as a colorless amorphous solid. 1H NMR (DMSO-d6,
600 MHz, δ, ppm) 9.67 (1H, broad s), 9.08 (1H, broad s), 3.70 (2H,
t, J =7.2 Hz), 3.07 (2H, m), 2.97 (2H, m), 2.73 (3H, d, J = 4.8 Hz),
2.46 (2H, m), 2.32 (2H, t, J = 7.8 Hz),1.58 (4H, m), 1.48 (2H,
quintet, J = 6.6 Hz), 1.27 (10H, m), 0.91 (3H, t, J = 7.2 Hz). 13
C
NMR (DMSO-d6, 125 MHz, δ, ppm) 172.96, 172.51, 54.90, 54.67,
43.42, 31.56, 31.48, 28.54, 28.51, 28.24, 25.77, 25.21, 23.96, 23.18,
19.19, 13.38. MS (FAB) m/z 331 (MHþ - HCl). HRMS calcd for
C16H35N2O4, 331.2598; found, 331.2597. HPLC tR = 16.00 min
(gradient (II), purity 96.5%).
3-({9-[Benzyl(methyl)]amino}nonanoyl(hydroxy)amino)propanoic
Acid Hydrochloride (15 HCl) and 3-({Hydroxy[9-(methylamino)-
nonanoyl]}amino)propanoicAcidHydrochloride(16 HCl). Step1:
3
3
Preparation of tert-Butyl 3-({9-[Benzyl(methyl)]amino}nonanoyl-
(benzyloxy)amino)propanoate (54). A solution of 26 (140 mg,
0.298 mmol) obtained above and benzylmethylamine (370 mg,
3.05 mmol) in MeCN (5 mL) was stirred at reflux temperature for
12 h. The reaction mixture was poured into water and extracted
with AcOEt. The organic layer was washed with brine and dried
over Na2SO4. Filtration, concentration in vacuo, and purification
by silica gel flash column chromatography (CHCl3/MeOH=30/1)
gave 113 mg (74%) of 54 as a yellow oil. 1H NMR (CDCl3, 600
MHz, δ, ppm) 7.38-7.29 (10H, m), 4.82 (2H, s), 3.91 (2H, m), 2.53
(2H, t, J = 6.6 Hz), 2.33 (4H, t, J = 7.8 Hz), 2.17 (3H, s), 1.56 (2H,
m), 1.49 (2H, m), 1.42 (9H, s), 1.26 (8H, m).
Steps 3 and 4: Preparation of 3-(N-Hydroxy-7-methyloctana-
mido)propanoic acid (12). Compound 12 was prepared from 45
obtained above using the procedure described for 4 (steps 3 and
1
4) in 38% yield as colorless crystals: mp 66-68 ꢀC. H NMR
(DMSO-d6, 500 MHz, δ; ppm) 3.70 (2H, t, J = 7.0 Hz), 2.45
(2H, t, J = 7.3 Hz), 2.31 (2H, t, J = 7.3 Hz), 1.53-1.46 (3H, m),
1.25-1.24 (4H, m), 1.16-1.12 (2H, m), 0.85 (6H, d, J = 6.7 Hz).
13C NMR (DMSO-d6, 125 MHz, δ, ppm) 173.13, 172.66, 43.51,
38.36, 31.70, 31.58, 29.06, 27.39, 26.64, 24.17, 22.53. MS (FAB)
m/z 246 (Mþ þ 1). Anal. Calcd for C12H23NO4: C, 58.75; H,
9.45; N, 5.71. Found: C, 58.51; H, 9.22; N, 5.86.
Step 2: Preparation of 3-({9-[Benzyl(methyl)]amino}nonanoyl
(hydroxy)amino)propanoic Acid Hydrochloride (15 HCl) and
3
tert-Butyl 3-({Hydroxy[9-(methylamino)nonanoyl]}amino)pro-
panoic Acid Hydrochloride (16 HCl). To a solution of 54
tert-Butyl 4-[(8-Dimethylaminooctyl)(hydroxyl)amino]-4-oxo-
butanoic Acid Hydrochloride (13 HCl). Step 1: Preparation of
tert-Butyl 4-[(Benzyloxy)amino]-4-oxobutanoate (48). A solution
3
(112 mg, 0.219 mmol) obtained above in 5 mL of AcOEt was
added 61 mg of 5% Pd/C. The mixture was stirred at room
3