2768 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 9
Uehling et al.
{2R-(tert-butoxycarbonyl)-[2R-(tert-butyldimethylsilyloxy)-2-(3-
chlorophenyl)ethyl]amino}acetaldehyde 5a (0.249 mg, 0.582 mmol)
were subjected to the above reductive amination procedure to give
the product (317 mg, 85% yield) as a yellow foam. Electrospray
MS (positive ion): (M + H) 639.8.
CD3OD): δ 1.30 (d, 3H, J ) 6.4), 3.05 (dd, 1H, J ) 12.4, 10.4),
3.26-3.37 (m, 3H); 3.61 (septet, 1H, J ) 6.4); 5.05 (dd, 1H, J )
10.4, 2.8); 6.60 (d, 1H, J ) 8.0); 6.80 (d, 1H, J ) 7.6); 6.91 (s,
1H), 7.12 (t, 1H, J ) 8.0); 7.24-7.34 (m, 6H), 7.40 (d, 1H, J )
8.8), 7.46 (s, 1H). Anal. (C24H25Cl1N2O3‚H2O): C, H, N.
3′-[[2R-[[2-(3-Chlorophenyl)-2R-hydroxyethyl]amino]propyl]-
amino]-[1,1′-biphenyl]-2,4-dicarboxylic Acid (34). 3′-[[2R-[[2-
(3-Chlorophenyl)-2R-[[(tert-butyl)dimethylsilyl]oxy]ethyl][(tert-
butoxy)carbonyl]amino]propyl]amino]-[1,1′-biphenyl]-2,4-dicar-
boxylic acid dimethyl ester 24 (655 mg, 0.92 mmol) was covered
with 4 N hydrochloric acid in 1,4-dioxane (5 mL) and stirred for
2 h. The mixture was concentrated with a rotary evaporator to leave
the hydroxylamine methyl ester HCl salt intermediate as an
uncharacterized semisolid residue, which was dissolved in MeOH
(3.0 mL) and treated with a solution of LiOH‚H2O (256 mg, 6.25
mmol) in H2O (1 mL). The mixture was stirred for 16 h and then
concentrated to leave the crude product as a lithium salt. Purification
by silica gel chromatography eluting with (60:40:2.2 CHCl3/MeOH/
concentrated NH4OH) gave product 34 as a yellow solid (302 mg,
70% overall) judged to be at least a 27:1 ratio of diastereomers
determined by the integration of the methyl doublets by 1H NMR.
3′-[((2R)-2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}-
propyl)amino]-3-biphenylcarboxylic Acid (37). A mixture of
methyl 3′-{[(2R)-2-(((2R)-2-(3-chlorophenyl)-2-{[(1,1-dimethylethyl)-
(dimethyl)silyl]oxy}ethyl){[(1,1-dimethylethyl)oxy]carbonyl}amino)-
propyl]amino}-3-biphenylcarboxylate 27 (1.90 g, 2.91 mmol) in 4
N HCl/dioxane (10 mL) was stirred for 5 h. The reaction mixture
was treated with Et2O (100 mL), and the resulting precipitate was
collected by suction filtration to afford, after drying in vacuo, the
hydroxylamine methyl ester HCl salt (1.35 g) as a white precipitate.
This material was dissolved in MeOH (16 mL), and a solution of
LiOH‚H2O (562 mg, 13.41 mmol) in H2O (5.5 mL) was added.
The resulting mixture was stirred at room temperature for 7 h and
concentrated with a rotary evaporator, and the residue was purified
by silica gel chromatography (75:15:1 CHCl3/MeOH/concentrated
NH4OH) to supply product 37 (867 mg, 72% overall yield) as a
white solid. An analysis of the methyl doublet by 1H NMR showed
this material to be a 4.6:1 ratio of diastereomers with the major as
the (R,R) isomer. 1H NMR (400 MHz, CD3OD) (37, major
diastereomer) δ 1.35 (d, 3H, J ) 6.4), 3.10 (dd, 1H, J ) 12.4,
10.0), 3.18 (dd, 1H, J ) 12.4, 3.2), 3.30-3.54 (m, 3H), 4.93 (dd,
1H, J ) 10.0, 3.2), 6.65 (d, 1H, J ) 7.6), 6.94 (d, 1H, J ) 6.8),
6.96 (s, 1H), 7.18 (t, 1H, J ) 8.0), 7.26-7.34 (m, 3H), 7.36 (t,
1H, J ) 7.6), 7.42 (s, 1H), 7.61 (d, 1H, J ) 7.6), 7.87 (d, 1H, J )
7.2), 8.17 (s, 1H). 13C NMR (100 MHz, DMSO-d6) (major
diastereomer): δ 17.70, 48.25, 52.62, 53.91, 70.64, 111.36, 112.01,
115.11, 125.31, 126.48, 127.54, 127.90, 128.61, 129.32, 130.25,
130.48, 130.55, 133.51, 134.65, 141.14, 141.64, 147.05, 150.00,
169.22. Anal. (C24H25Cl1N2O3‚1H2O): C, H, N.
(R)-3′-[[2-[[2-(3-Chlorophenyl)-2-hydroxyethyl]amino]ethyl]-
amino]-[1,1′-biphenyl]-3-carboxylic Acid (38). (a). (R)-3′-[[2-[[2-
(3-Chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1′-bi-
phenyl]-3-carboxylic Acid Methyl Ester Dihydrochloride (39).
A solution of (R)-3′-[[2-[[2-(3-chlorophenyl)-2-[[(tert-butyl)di-
methylsilyl]oxy]ethyl][(tert-butoxy)carbonyl]amino]ethyl]amino]-[1,1′-
biphenyl]-3-carboxylic acid methyl ester (23.8 g, 37.2 mmol mg)
in 4 N hydrochloric acid in dioxane (80 mL) was stirred for 3 h.
Diethyl ether was added, and the mixture was stirred for 20 min.
The resulting solid was collected by suction filtration to afford 15.72
g (92% yield) of the product as a white solid. C24H25Cl1N2O3: MH+
calcd, 425.1632; found, 425.1635 ∆0.3 mmu. 1H NMR (400 MHz,
DMSO-d6) δ 3.00-3.30 (m, 4H), 3.47 (t, 2H, J ) 6.4), 3.85 (s,
3H), 4.20 (bs, 2H), 4.97 (d, 1H, J ) 10.0), 6.67 (d, 1H, J ) 7.2),
6.87 (d, 1H, J ) 7.2), 6.89 (s, 1H), 7.21 (t, 1H, J ) 8.0), 7.32-
7.39 (m, 3H), 7.43 (s, 1H), 7.57 (t, 1H, J ) 8.0), 7.86 (d, 1H, J )
7.6), 7.90 (d, 1H, J ) 7.6), 8.10 (s, 1H).
(b). (R)-3′-[[2-[[2-(3-Chlorophenyl)-2-hydroxyethyl]amino]eth-
yl]amino]-[1,1′-biphenyl]-3-carboxylic Acid (38). To a solution
of the (R)-3′-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-
amino]-[1,1′-biphenyl]-3-carboxylic acid methyl ester hydrochloride
(4.12 g) in MeOH (60 mL) was added a solution of LiOH‚H2O
(2.08 g) in water (20 mL). The mixture was stirred for 16 h, and
1 N hydrochloric acid was added until the mixture was neutral.
The mixture was decanted, and the residue was purified by flash
silica chromatography eluting with 6:2:0.1 CHCl3/MeOH/concen-
trated NH4OH to afford a viscous oil. Trituration with ether and
washing with water afforded product 38 as a white solid (2.22 g).
1H NMR (400 MHz, CD3OD) δ 3.09 (dd, 1H, J ) 12.4, 10.0),
3.23 (m, 1H), 3.25 (t, 2H, J ) 6.0) 3.50 (t, 2H, J ) 6.0), 4.97 (dd,
1H, J ) 10.0, 3.2), 6.59 (s, 1H), 6.62 (d, 1H, J ) 8.0), 6.66 (d,
1H, J ) 8.0), 7.17 (t, 1H, J ) 7.6), 7.22 (d, 1H, J ) 8.0), 7.28-
7.33 (m, 3H), 7.45 (s, 1H), 7.78 s, 1H), 7.79 (t, 1H, J ) 7.6). 13C
NMR (100 MHz, DMSO-d6) δ 42.49, 48.10, 56.69, 70.70, 111.21,
112.07, 115.09, 125.30, 126.45, 127.53, 127.88, 128.61, 129.42,
130.27, 130.58, 130.72, 133.50, 141.08, 141.74, 147.17, 149.95,
168.92. C23H23Cl1N2O3: MH+ calcd, 411.1475; found, 411.1495.
Anal. (C23H23Cl1N2O3‚0.46H2O): C, H, N.
1
Electrospray MS (positive ion): (M + H) 469.1. H NMR (400
MHz, DMSO-d6): δ 1.13 (d, 3H, J ) 6.0), 2.79 (t, 1H, J ) 10.0),
3.03 (m, 2H), 3.21 (m, 2H), 5.07 (d, 1H, J ) 7.6), 5.80 (bs, 1H),
6.55 (d, 1H, J ) 8.0), 6.64 (d, 1H, J ) 8.0), 6.97 (s, 1H), 7.06 (t,
1H, J ) 7.6), 7.27-7.35 (m, 4H), 7.44 (s, 1H), 7.80 (dd, 1H, J )
8.0, 1.6), 7.88 (d, 1H, J ) 1.6). HPLC (C18): 94.2% purity, 8.71
min retention time using a 30-80% acetonitrile-water with 0.1%
trifluoroacetic acid gradient mobile phase with detection by
absorbance at 254 nM. Anal. (C25H25Cl1N2O5‚2H2O): C, H, N.
3′-[[2R-[[2-(3-Chlorophenyl)-2R-hydroxyethyl]amino]propyl]-
amino]-[1,1′-biphenyl]-4-carboxylic Acid (35). A mixture of 3′-
[[2R-[[2-(3-chlorophenyl)-2R-[[(tert-butyl)dimethylsilyl]oxy]ethyl]-
[(tert-butoxy)carbonyl]amino]propyl]amino]-[1,1′-biphenyl]-4-
carboxylic acid methyl ester 25 (289 mg, 0.45 mmol) in 4 N
hydrochloric acid in 1,4-dioxane (4 mL) was stirred for 1.5 h. The
mixture was diluted with Et2O and stirred for 20 min to give a
viscous residue. The solvent was decanted from the residue, and
the residue was dried under vacuum. This material was dissolved
in 3:1 MeOH/H2O (10 mL), treated with LiOH‚H2O (120 mg, 2.86
mmol), and stirred overnight. The mixture was concentrated under
reduced pressure and chromatographed on silica eluting with
MeOH/CH2Cl2/88% NH4OH (15:85:1.5) to give the title compound
1
as a white solid (31 mg, 18% yield), judged by H NMR to be at
least a 25:1 mixture of diastereomers determined by the integration
of the methyl doublets. Electrospray MS (positive ion): (M + H)
425.0. HPLC (C18): 98.35% purity, 12.7 min retention time using
1
a 10-100% acetonitrile-water with 0.1% trifluoroacetic acid. H
NMR (300 MHz, DMSO-d6): δ 1.13 (d, 1H, J ) 6.0), 2.81-2.93
(m, 2H), 3.08-3.30 (m, 5H), 4.79 (dd, 1H, J ) 8.7, 3.6), 5.85 (bs,
1H), 6.61 (d, 1H, J ) 8.4), 6.84 (d, 1H, J ) 7.8), 6.90 (s, 1H, 7.16
(t, 1H, J ) 7.8), 7.27-7.34 (m, 5H), 7.42 (s, 1H), 7.61 (d, 1H, J
) 8.4), 7.98 (d, 1H, J ) 8.1).
3′-[((2R)-2-{[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino}-
propyl)amino]-2-biphenylcarboxylic Acid (36). A mixture of
methyl 3′-{[(2R)-2-(((2R)-2-(3-chlorophenyl)-2-{[(1,1-dimethylethyl)-
(dimethyl)silyl]oxy}ethyl){[(1,1-dimethylethyl)oxy]carbonyl}amino)-
propyl]amino}-2-biphenylcarboxylate 26 (6.89 g, 10.55 mmol) and
4 N HCl/dioxane (40 mL) was stirred at room temperature for 2 h.
The mixture was concentrated to ca. 50% volume with a rotary
evaporator, and Et2O was added to supply the intermediate
hydroxyphenylethylamine methyl ester hydrochloride (5.34 g) as
a white solid. This material was dissolved in MeOH (63 mL), and
3.68 g (87.8 mmol) of LiOH‚H2O in H2O (21 mL) was added. The
mixture was heated at 45 °C for 16 h. The mixture was allowed to
cool to room temperature and concentrated with a rotary evaporator.
Purification of the residue by silica gel chromatography (92:15:1
to 30:15:1 CHCl3/MeOH/concentrated NH4OH) afforded 2.0 g (45%
yield) of product 36 as a white solid, judged by 1H NMR integration
of the methyl doublet to be a 4.6:1 mixture of diastereomers.
Electrospray MS (positive ion): (M + H) 425. 1H NMR (400 MHz,