PradefoVir
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 3 671
1-(2-Fluorophenyl)-1,3-propanediol (6d). 1H NMR (200 MHz,
CDCl3): δ 7.52 (td, J ) 6.2, 0.8 Hz, 1H) 7.3–6.9 (m, 3H), 5.25 (t,
J ) 6.2 Hz, 1H), 3.84 (t, J ) 5.1 Hz, 2H), 3.5 (br s, 1H), 2.8 (br
s, 1H), 1.97 (dd, J ) 6.2, 5.1 Hz, 2H).
kidney exposure ratio relative to ADP. The mesylate salt of
prodrug 14, which was selected as the development candidate
based on its improved oral bioavailability in the rat, is currently
under clinical evaluation in hepatitis B patients.19
1-(2-Chlorophenyl)-1,3-propanediol (6e). 1H NMR (200 MHz,
CDCl3): δ 7.63 (d, J ) 7.0 Hz, 1H) 7.39–7.15 (m, 3H), 5.35 (dd,
J ) 8.4, 2.7 Hz, 1H), 3.90 (br s, 1H), 3.22 (br s, 1H), 2.42 (br s,
1H), 2.15–1.80 (m, 2H).
Experimental Section
General Information. Glassware for moisture-sensitive reactions
was flame-dried and cooled to room temperature in a desiccator,
and all reactions were carried out under an atmosphere of nitrogen.
Anhydrous solvents were purchased from Aldrich or Acros. Thin
layer chromatography was performed on EM Science silica gel 60
F254 plates and was visualized with a UV lamp (254 nm) or cerium
stain. Column chromatography was performed on 230–400 mesh
EM Science silica gel 60. Melting points were recorded on a
Thomas-Hoover capillary melting point apparatus and are uncor-
rected. 1H and 13C NMR spectra were obtained on a Varian Gemini-
200 operating at 200 and 50 MHz, respectively, or a Varian
1-(2-Bromophenyl)-1,3-propanediol (6f). 1H NMR (300 MHz,
DMSO-d6): δ 7.60–7.53 (m, 2H) 7.43–7.37 (m, 1H), 7.21–7.16 (m,
1H), 5.36–5.35 (m, 1H), 4.95–4.91 (m, 1H), 4.49–4.46 (m, 1H),
3.61–3.35 (m, 2H), 1.79–1.58 (m, 2H).
1-(3-Fluorophenyl)-1,3-propanediol (6g). 1H NMR (200 MHz,
CDCl3): δ 7.22 (dd, J ) 12.0, 8.0 Hz, 1H), 7.09–6.98 (m, 2H),
6.89 (td, J ) 12.0, 2.2 Hz, 1H), 4.84 (br d, J ) 4.4 Hz, 1H), 4.30
(br s, 1H), 3.73 (br d, J ) 4.4 Hz, 2H), 3.40 (br s, 1H), 1.84 (dd,
J ) 6.4, 5.0 Hz, 2H).
1-(3-Chlorophenyl)-1,3-propanediol (6h). 1H NMR (200 MHz,
CDCl3): δ 7.40–7.18 (m, 4H), 5.00–4.90 (dd, J ) 6.8, 6.1 Hz, 1H),
3.85 (t, J ) 5.8 Hz, 2H), 2.40 (s, 2H), 2.00–1.90 (m, 2H).
1-(3-Bromophenyl)-1,3-propanediol (6i). 1H NMR (300 MHz,
DMSO-d6): δ 7.53 (s, 1H), 7.45–7.40 (m, 1H), 7.35–7.25 (m, 2H),
5.30 (d, J ) 4.5 Hz, 1H exchangeable with D2O), 4.73–4.63 (m,
1H), 4.47 (t, J ) 5.1 Hz, 1H exchangeable with D2O), 3.60–3.35
(m, 2H), 1.85–1.65 (m, 2H).
1
Mercury-300 operating at 300 and 75 MHz, respectively. H and
13C NMR spectra were recorded in δ units using the solvent’s
chemical shift as the reference line. 1H NMR data for only
characteristic signals are provided where a mixture of prodrug
isomers was characterized, whereas complete characterization is
presented in the case of single isomer prodrugs. C, H, N micro-
analyses were performed by Robertson Microlit Laboratories, Inc.,
Madison, NJ, or by NuMega Resonance Laboratories, Inc., San
Diego, CA. All protocols involving animal experimentation were
reviewed and approved by the Metabasis Therapeutics IACUC
(Institution Animal Care and Use Committee) and follow the
guidelines established by the NRC “Guide for the Care and Use of
Laboratory Animals”.
1-(2,3-Difluorophenyl)-1,3-propanediol (6j). 1H NMR (200
MHz, CDCl3): δ 7.30 (m, 1H), 7.15–7.00 (m, 2H), 5.28 (t, J ) 5.9
Hz, 1H), 3.87 (t, J ) 5.1 Hz, 2H), 3.61 (br s, 1H), 2.63 (br s, 1H),
1.99 (m, 2H).
1-(2,4-Difluorophenyl)-1,3-propanediol (6k). 1H NMR (200
MHz, CDCl3): δ 7.45 (t, d, J ) 8.6, 6.6 Hz, 1H), 6.92–6.69 (m,
2H), 5.19 (dd, J ) 5.8, 4.0 Hz, 1H), 3.83 (br s, 2H), 3.72 (br s,
1H), 2.90 (br s, 1H) 1.93 (q, J ) 6.0 Hz, 2H).
General Procedure for Preparation of Racemic 1-Aryl
Substituted Propane-1,3-diols 6a–z. Step A. To a solution of
diisopropylamine (2 mmol) in THF (0.7 mL/mmol diisopropyl-
amine) at -78 °C was slowly added a solution of n-BuLi (2 mmol,
2.5 M in hexanes). The mixture was then stirred for 15 min at -78
°C before a solution of ethyl acetate (2 mmol) in THF (0.14 mL/
mmol ethyl acetate) was slowly introduced. After the mixture was
stirred for an additional 30 min at -78 °C, a THF solution
containing the aryl aldehyde (1.0 mmol in 0.28 mL of THF) was
added. The mixture was then stirred at -78 °C for 30 min, warmed
to room temperature, and stirred an additional 2 h. After aqueous
workup (0.5 M HCl), the organic layer was concentrated to a crude
oil and purified either by chromatography or by distillation.
Step B. LiAlH4 Reduction of ꢀ-Hydroxy Esters. A solution
of hydroxyester (1 mmol) in ether (1 M) was added to a suspension
of LiAlH4 (3 mmol) in ether (1 M) at 0 °C. The mixture was stirred,
allowing the cooling bath to melt and the mixture to reach room
temperature. Once the reaction was judged complete (TLC), the
reaction mixture was cooled back to 0 °C and quenched with ethyl
acetate. Aqueous workup (0.5 M HCl) afforded the crude diol,
which was purified by chromatography or distillation.
1-(2,5-Difluorophenyl)-1,3-propanediol (6l). 1H NMR (200
MHz, CDCl3): δ 7.27 (td, J ) 5.8, 2.7 Hz, 1H), 7.02–6.82 (m,
2H), 5.24 (dd, J ) 7.6, 4.0 Hz, 1H), 3.89 (t, J ) 6.6 Hz, 2H), 2.57
(br s, 2H), 2.04–1.91 (m, 2H).
1-(2,6-Difluorophenyl))-1,3-propanediol (6m). 1H NMR (200
MHz, CDCl3): δ 7.22 (d, J ) 8.4 Hz, 2H), 6.88 (t, J ) 8.4 Hz,
1H), 5.32 (dd, J ) 9.0, 4.0 Hz, 1H), 3.89 (td, J ) 5.9, 5.3 Hz, 2H),
2.36–1.90 (m, 4H).
1-(3,5-Difluorophenyl)-1,3-propanediol (6n). 1H NMR (200
MHz, CDCl3): δ 7.24–7.07 (m, 1H), 6.90 (dd, J ) 8.4, 1.8 Hz,
1H), 6.70 (tt, J ) 8.4, 1.8 Hz, 1H), 4.94 (dd, J ) 12.0, 5.8 Hz,
1H), 3.88 (t, J ) 5.8 Hz, 2H), 2.36 (br s, 2H), 1.93 (m, 2H).
1
1-(2,3-Dichlorophenyl))-1,3-propanediol (6o). H NMR (200
MHz, CDCl3): δ 7.54 (dd, J ) 7.4, 1.6 Hz, 1H), 7.35 (dd, J ) 7.4,
1.6 Hz, 1H), 7.27 (t, J ) 7.4 Hz, 1H), 5.33 (d, J ) 8.8 Hz, 1H),
3.88 (br s, 2H), 3.77 (br s, 1H), 2.72 (br s, 1H), 2.15–1.75 (m,
2H).
1-(2,4-Dichlorophenyl)-1,3-propanediol (6p). 1H NMR (200
MHz, C6D6): δ 7.60 (d, J ) 8.0 Hz, 1H), 7.35–7.27 (m, 2H), 5.32
(dd, J ) 8.4, 3.0 Hz, 1H), 3.94 (td, J ) 5.6, 2.2 Hz, 2H), 2.30–1.80
(m, 4H).
NaBH4 Reduction of ꢀ-Hydroxy Esters. NaBH4 was added
portionwise to a solution of hydroxyester in EtOH at room
temperature. After 20 min the heterogeneous white reaction mixture
was heated to reflux until all starting material was consumed (3–5
h, TLC). The cooled mixture was concentrated under reduced
pressure and partitioned between water and EtOAc. The layers were
separated, and the aqueous layer was back-extracted with EtOAc.
The combined extracts were dried (Na2SO4), concentrated under
reduced pressure, and purified by chromatography on silica gel to
give the corresponding diol. Typical overall yields of diols for two
steps were 40-80%.
1-(2,6-Dichlorophenyl)-1,3-propanediol (6q). 1H NMR (200
MHz, CDCl3): δ 7.32 (d, J ) 13.6 Hz, 2H), 7.14 (t, J ) 13.6 Hz,
1H), 5.66 (dd, J ) 9.8, 4.0 Hz, 1H), 3.90 (t, J ) 6.0 Hz, 2H),
2.55–2.36 (m, 3H), 1.95 (dq, J ) 14.6, 4.4 Hz, 1H).
1-(3,4-Dichlorophenyl)-1,3-propanediol (6r). 1H NMR (200
MHz, CDCl3): δ 7.47 (d, J ) 2.2 Hz, 1H), 7.41 (d, J ) 8.4 Hz,
1H), 7.17 (dd, J ) 8.4, 2.2 Hz, 1H), 4.92 (dd, J ) 6.6, 5.8 Hz,
1H), 3.86 (t, J ) 5.0 Hz, 2H), 2.75 (br s, 2H), 1.91 (dd, J ) 10.8,
5.6 Hz, 2H).
1-(3,5-Dichlorophenyl)-1,3-propanediol (6s). 1H NMR (300
MHz, DMSO-d6) δ 7.43 (s, 1H), 7.32 (s, 2H), 5.40 (d, J ) 4.5 Hz,
1H exchangeable with D2O), 4.60–4.75 (m, 1H), 4.44 (t, J ) 5.1
Hz, 1H exchangeable with D2O), 3.55–3.31 (m, 2H), 1.77–1.60
(m, 2H).
1
1-(3,5-Dimethylphenyl)-1,3-propanediol (6b). H NMR (200
MHz, CDCl3): δ 6.98 (s, 2H), 6.93 (s, 1H), 4.89 (dd, J ) 8.2, 4.8
Hz, 1H), 3.85 (dd, J ) 6.8, 6.1 Hz, 2H), 2.49 (br s, 2H), 2.32 (s,
6H), 2.10–1.81 (m, 1H).
1-(4-tert-Butylphenyl)-1,3-propanediol (6c). 1H NMR (200
MHz, CDCl3): δ 7.41–7.28 (m, 4H), 4.95 (dt, J ) 9.5, 3.4 Hz,
1H), 3.87 (q, J ) 6.1 Hz, 2H), 2.56 (d, J ) 3.4 Hz, 1H), 2.31 (t,
J ) 6.1 Hz, 1H), 2.10–1.85 (m, 1H).
1-(2-Bromo-5-methoxyphenyl)-1,3-propanediol (6t). 1H NMR
(200 MHz, CDCl3): δ 7.36 (dd, J ) 8.8, 0.8 Hz, 1H), 7.18 (d, J )
3.2 Hz, 1H), 6.68 (ddd, J ) 8.8, 3.2, 0.8 Hz, 1H), 5.21 (br d, J )