Synthesis of a novel tricyclic 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline ring system and CXCR4 antagonists with potent activity against HIV-1

Article abstract of DOI:10.1016/j.bmcl.2010.02.030

Stereorandom and diastereoselective syntheses of a novel 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline ring system are described. Derivatives of all four diastereomers were prepared and isolated in >98% ee. The pure enantiomers were compared in order t

Full text of DOI:10.1016/j.bmcl.2010.02.030

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2186–2190
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of a novel tricyclic 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline
ring system and CXCR4 antagonists with potent activity against HIV-1
a
a
a
a
John G. Catalano a, , Kristjan S. Gudmundsson , Angilique Svolto , Sharon D. Boggs , John F. Miller ,
Andrew Spaltenstein a, Michael Thomson b, Pat Wheelan c, Doug J. Minick d, Dean P. Phelps d,
Stephen Jenkinson e
*
a Department of Medicinal Chemistry, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline Research & Development, Five Moore Drive,
Research Triangle Park, NC 27709-3398, USA
b Department of Virology, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline Research & Development, Five Moore Drive, Research Triangle Park,
NC 27709-3398, USA
c Department of DMPK, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline Research & Development, Five Moore Drive, Research Triangle Park,
NC 27709-3398, USA
d Department of Analytical Chemistry, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline Research & Development, Five Moore Drive,
Research Triangle Park, NC 27709-3398, USA
e Department of Biochemical and Analytical Pharmacology, Infectious Diseases Center of Excellence for Drug Discovery, GlaxoSmithKline Research & Development,
Five Moore Drive, Research Triangle Park, NC 27709-3398, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereorandom and diastereoselective syntheses of a novel 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthro-
line ring system are described. Derivatives of all four diastereomers were prepared and isolated in >98%
ee. The pure enantiomers were compared in order to determine the preferred absolute and relative con-
figuration required for optimal anti-HIV activity. Anti-HIV potency and pharmacokinetic properties of the
newly synthesized tricyclic octahydrophenanthroline inhibitors are presented and comparisons are made
to previously reported bicyclic (8S)-N-methyl-5,6,7,8-tetrahydro-8-quinolinamine analogs.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 8 January 2010
Revised 4 February 2010
Accepted 8 February 2010
Available online 12 February 2010
Keywords:
CXCR4
HIV
AIDS
Inhibitor
Antiviral
Viral
Entry
Chemokine
CXCR4 is a G-protein coupled seven-transmembrane spanning
receptor that has the rare characteristic of having only one known
natural ligand, stromal cell-derived factor (SDF-1).1 SDF-1 is a highly
basic protein with about 20% of its 68 amino acids containing basic
side-chains. CXCR4 is somewhat unusual among chemokine recep-
tors in that it is strongly negatively charged. Recently there has been
significant interest in CXCR4 inhibitors for the treatment of cancer,
stem cell mobilization,2 and HIV inhibition. CXCR4 is known to be
a co-receptor for a number of specific strains of HIV-1,3 and SDF-1
has been shownto inhibitinfection of CD4+ cells by X4 HIV strains.4,5
Furthermore, several classes of highly basic small molecule CXCR4
inhibitors have been reported in the literature to have anti-HIV
activity.6–10 HIV/AIDS continues to be a threat to public health. Po-
tential treatments with new modes of action should be especially
beneficial to clinicians struggling to treat patients with resistant
HIV strains.
Our group previously reported examples of benzimidazole and
imidazopyridine CXCR4 inhibitors,
1
and 2a, respectively
(Fig. 1).9,10 In each series the benzimidazole/imidazopyridine core
was substituted with a tethered basic amine side-chain, such as
the 3-dimethylaminopropyl group shown for benzimidazole 1 or
the N-methylpiperazine shown for imidazopyridine 2a. Both the
benzimidazole/imidazopyridine cores were additionally linked to
the 8-position of a 5,6,7,8-tetrahydroquinoline ring system through
a central unconstrained tertiary methyl amino moiety. As an evolu-
tionof thisearlierwork, wesoughttoconformationallyrestrainrota-
tion about the 8-amino group of the bicyclic tetrahydroquinoline
core by incorporating a novel tricyclic octahydrophenanthroline
ring system.
The octahydrophenanthroline ring system encompasses four
distinct stereoisomers and represents a previously unreported
* Corresponding author. Tel.: +1 919 483 6264.
E-mail address: john.g.catalano@gsk.com (J.G. Catalano).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.02.030

J. G. Catalano et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2186–2190
2187
trile gave nitrile 4. Reduction of nitrile 4 with Raney nickel at 70 °C
under 50–60 psi of hydrogen led to spontaneous cyclization via
intramolecular reductive amination to afford the desired
N
N
N
N
N
1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline
5.Octahydro-
N
N
N
N
phenanthroline 5 was carried forward as a mixture of diastereomers
(2.6:1 cis/trans) and was condensed with N-Boc-2-chloromethyl
benzimidazole.14 At this stage, achiral chromatography gave two
pairs of enantiomers with cis and trans relative configurations about
the octahydrophenanthroline core. The unresolved pairs of enantio-
mers were carried forward separately. Removal of the t-butyl carba-
mate protecting group gave benzimidazole 6, and the amine side-
chain was incorporated by alkylation to give final products 7. Re-
solved compounds 7a–d were obtained via chiral reverse phase
HPLC of the corresponding racemic mixtures.15 Absolute stereo-
chemistry was assigned by Ab Initio Vibrational Circular Dichroism
(VCD) Spectroscopy.16,17
Testing for anti-HIV activity revealed that cis analog 7a was the
most potent of the isomers (Fig. 2). Compound 7a had an IC50 of
35 nM against HIV-1 and was essentially equipotent to the analo-
gous bicyclic tetrahydroquinoline derivative 1. Activity for the cis
isomer 7b fell off more than 15-fold. Both trans diastereomers 7c
and 7d were also less potent. An obvious preference for the S config-
uration at the 10b position was observed for both the cis and trans
diastereomers, 7a and 7c, respectively, which was consistent with
the preference for S-stereochemistry of tetrahydroquinoline 1.
Having determined that the (4aR,10bS)-configuration of struc-
ture 7a was the preferred replacement for the (8S)-N-methyl-
5,6,7,8-tetrahydro-8-quinolinamine moiety of 1, we developed a
route to the favored cis diastereomer (Scheme 2). We also chose
to incorporate the preferred imidazopyridine moiety found in com-
pound 2a. A pyrrolidine enamine was formed by reacting ketone 3
with pyrrolidine under Dean–Stark conditions and the resulting
enamine reacted with ethyl acrylate to give keto ester 8. Reductive
amination with (S)-1-(4-methyloxyphenyl)ethylamine afforded
the desired cis diastereomer 9 in good yield. Diastereomeric and
enantiomeric control of reductive aminations between racemic
N
N
N
N
1
2a
IC50 = 9.8 nM
IC50 = 2.0 nM
Figure 1.
scaffold. Our initial strategy was to target the ring system by achi-
ral synthetic methods in order to obtain all four possible stereoiso-
mers (Scheme 1). Subsequent resolution via chiral chromatography
would then allow us to test single compounds.
The 6,7-dihydro-8(5H)-quinolinone 3 was synthesized by con-
densation of propargylamine with 1,2-cyclohexadione using condi-
tions developed by Abbiati et al.11 Although yields were generally
poor, commercially available starting materials for this scalable
one-step method were fairly inexpensive and isolation of the result-
ing ketone 3 was straight-forward.12 Ketone 3 is now commercially
available and several multi-step methods for its preparation have
been reported.13 The enolate of ketone 3 was formed by deprotona-
tion with LDA and subsequent treatment of the anion with acryloni-
a
b
H2N
O
N
CN
N
O
O
O
3
4
c
a
-substituted cyclohexanones and chiral a-methylbenzylamines
6
7
are precedented.18 The ester 9 was reduced with lithium alumi-
num hydride to give alcohol 10. Treatment of 10 with methanesul-
fonyl chloride led to spontaneous cyclization and yielded the
desired protected tricyclic octahydrophenanthroline ring system
11. Deprotection with trifluoroacetic acid gave amine 12, which
was alkylated with 2-(chloromethyl)-5-fluoroimidazo[1,2-a]pyri-
dine19 to give the penultimate 5-fluoroimidazo[1,2-a]pyridine
intermediate 13. Final targets, such as 14a20, were realized by
treating 13 with preferred amines.
N
N
N
5
8
9
N
N
4a
4
N
f
d, e
N
N
NH
HN
1
10b
3
N
2
2.6 : 1 cis/trans
7
6
5
Scheme 1. Reagents and conditions: (a) Na2AuCl4 dihydrate, EtOH, 75 °C, 24 h, (20–
25%); (b) i-Pr2NH, n-BuLi, THF, À78 °C, 1.5 h, then acrylonitrile, À78 °C to 40 °C,
16 h, (72%); (c) Raney nickel, EtOH, H2 (60 psi), 70 °C, 16 h, (43%); (d) N-Boc-2-
chloromethyl benzimidazole, K2CO3, KI, CH3CN, rt, 16 h; (e) TFA, CH2Cl2, 2 h, RT;
(80–90%); (f) Cl(CH2)3NMe2, K2CO3, KI, DMF, 80 °C, 16 h, (52–63%).
The cis antipode 14b (Fig. 3) was obtained by following Scheme
2, but using (R)-1-(4-methyloxyphenyl)ethylamine for the reduc-
tive amination in step b. The single trans diastereomer 14c was ob-
H
H
H
H
N
N
N
N
N
N
N
N
H
H
H
H
N
N
N
N
N
N
N
N
N
N
N
N
7a
IC50 = 35 nM
CC50 = 6000 nM
7b
IC50 = 530 nM
CC50 = 4200 nM
7c
7d
IC50 = 140 nM
CC50 = 3500 nM
IC50 = 330 nM
CC50 = 3700 nM
Figure 2. Comparison of anti-HIV activity between diastereomers of the benzimidazole series. HOS cells (expressing hCXCR4/hCCR5/hCD4/pHIV-LTR-luciferase), HIV-1, T-tropic
CXCR4 strain (IIIB). Compounds were tested for their ability to block infection of the HOS cell line. IC50 is the concentration at which 50% efficacy in the antiviral assay is observed.
CC50 is the concentration at which 50% cytotoxicity is observed in the HOS cell line.

2188
J. G. Catalano et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2186–2190
H
a
b
O
O
N
N
H
N
O
NH
O
O
O
3
8
9
O
H
H
N
N
H
O
H
O
N
NH
OH
H
c
d
e
N
H
HN
11
10
12
H
H
N
N
N
H
H
N
N
f
g
N
N
N
F
N
N
13
14a
Figure 4. ORTEP diagram of 1-{[5-(4-methyl-1-piperazinyl)imidazo[1,2-a]pyri-
dine-2-yl]methyl}1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline 14a showing
atomic numbering scheme and 50% anisotropic displacement ellipsoids for non-
hydrogen atoms. Hydrogen atoms are displayed with an arbitrarily small radius.
Cambridge Crystallographic Data Centre deposition number CCDC 760486.21
Scheme 2. Reagents and conditions: (a) (i) pyrrolidine, p-TosOH, benzene, reflux,
Dean–Stark, 4 h; (ii) ethyl acrylate, ethanol, reflux, 6 h, then H2O, 78 °C, 4 h (58%);
(b) (i) (1S)-1-[4-(methyloxy)phenyl]ethanamine, p-TosOH, toluene, Dean–Stark,
4 h, (ii) NaBH(OAc)3, 1,2-DCE, 16 h (61%); (c) LiAlH4, THF, 0 °C, 1 h (64%); (d) MsCl, i-
Pr2NEt, DMAP, CH2Cl2, 16 h, (98%); (e) TFA, CH2Cl2, 2 h; (98%); (f) 2-(chloromethyl)-
5-fluoroimidazo[1,2-a]pyridine, K2CO3, KI, CH3CN, RT, 16 h (56%); (g) 1-methylpi-
perazine, DMSO, 60 °C, 16 h, (63%).
core, the imidazopyridine example 14a was equipotent with the
previously reported bicyclic derivative 2a.
tained by carrying a minor trans by-product to the final stage of
Scheme 2, and then isolating by silica gel chromatography. The
(+/-) trans mixture 14d was obtained by following the achiral
route, but replacing the benzimidazole core in Scheme 1 with the
imidazopyridine core. Absolute configuration for 14a was tenta-
tively assigned by Ab Initio Vibrational Circular Dichroism (VCD)
Spectroscopy and then confirmed by X-ray crystallography
(Fig. 4).16,17,21
The SAR trend for the imidazopyridine diastereomers 14a–d
(Fig. 3) was consistent with that observed for benzimidazole dia-
stereomers 7a–d. The (4aR,10bS)-configuration was preferred over
the other isomers in both series. Imidazopyridine analog 14a was
50-fold more potent than antipode 14b and roughly 25-fold more
potent than the single trans diastereomer 14c. The racemic trans
mixture 14d was equipotent to 14c, indicating that the antipode
to 14c was less potent or equipotent. As with the benzimidazole
A number of additional compounds were synthesized in order
to further compare tricyclic octahydrophenanthroline derivatives,
14a and 14e–k, to previously reported bicyclic tetrahydroquinoline
analogs 2a–h9 (Table 1). The subset of comparable analogs pre-
sented in Table 1 demonstrates that SAR tracked fairly well be-
tween the two series, regardless of overall potency. Potent
analogs such as 2a and 14a had very similar anti-HIV activity, as
did the much less potent morpholine derivatives 2b and 14e. The
R-group entries in Table 1 all impart less than a fourfold potency
difference between comparable analogs of the two series. No clear
general preference for either core was observed and this trend in
SAR generally held true throughout a much broader series of sim-
ilar analogs that are not presented herein. Overall, the anti-HIV
activity of the tricyclic analogs (14a, 14e–k) compared with the
tetrahydroquinolines (2a–h), establishing the tricyclic core as a
H
H
H
H
trans
N
N
N
N
N
N
N
N
H
H
H
H
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
14a
14b
14c
14d
IC50 = 100 nM
CC50 = 8500 nM
IC50 = 50 nM
CC50 = 9900 nM
IC50 = 32 nM
CC50 = 9600 nM
IC50 = 2.0 nM
CC50 = 9600 nM
Figure 3. Anti-HIV activity of 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline diastereomers. HOS cells (expressing hCXCR4/hCCR5/hCD4/pHIV-LTR-luciferase), HIV-1, T-
tropic CXCR4 strain (IIIB). Compounds were tested for their ability to block infection of the HOS cell line. IC50 is the concentration at which 50% efficacy in the antiviral assay is
observed. CC50 is the concentration at which 50% cytotoxicity is observed in the HOS cell line.

J. G. Catalano et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2186–2190
2189
Table 1
Anti-HIV activity of imidazopyridine-1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline derivatives compared to imidazopyridine-tetrahydro-8-quinolinamine derivatives
H
N
N
N
N
H
N
N
b
b
c
R
IC50 (nM)
IC50 (nM)
CC50 (nM)
N
N
R
R
N
N
Me
2aa
2ba
2ca
2da
2.0
690
17
14a
14e
14f
14g
2.0
9500
6600
1450
3850
N
O
1200
5.0
N
N
N
NMe2
Me
4.0
15
N
2ea
2fa
30
49
14h
14i
9.0
38
1570
1300
N
Me
N
Me
N
Me
N
N
2ga
2.0
8.0
14j
2.0
21
2980
1600
N
2ha
14k
NMe2
Compounds with data were reported previously.10
a
b
HOS cells (expressing hCXCR4/hCCR5/hCD4/pHIV-LTR-luciferase), HIV-1, T-tropic CXCR4 strain (IIIB). Compounds were tested for their ability to block infection of the
HOS cell line. IC50 is the concentration at which 50% efficacy in the antiviral assay is observed.
c
CC50 is the concentration at which 50% cytotoxicity is observed in the HOS cell line. CC50 data for compounds 2a–h were reported previously.10
Table 2
to the bicyclic (8S)-N-methyl-5,6,7,8-tetrahydro-8-quinolinamine
Pharmacokinetic data for imidazopyridien-1,2,3,4,4a,5,6,10b-octahydro-1,10-phe-
nanthroline derivative compared to imidazopyridine-tetrahydro-8-quinolinamine
derivative
core. GiventhesimilarSARprofilebetweenthesetwocores, wespec-
ulate that the tetrahydroquinoline scaffold efficiently adopts a con-
formation similar to that of the more restricted octahydro
phenanthroline system. So although significant gains in potency
were not realized by restricting conformational rotation, metabolic
stability seems to have been positively affected. Further studies
showed that 14a displayed a suitable cytochrome P450 profile and
screening against a panel of enzymes and receptors (Panlabs) re-
vealed little risk of unwanted enzyme and receptor inhibition. Be-
cause of the promising anti-HIV potency and oral bioavailability,
compound 14a was progressed into toxicology studies and served
as a novel core for synthesis of additional analogs.
Compound
Species
2a
Rat
14a
Rat
2a
Dog
14a
Dog
Cl (mL/min/kg)
Vdss (L/kg)
T1/2 (h)
F (%, solution)
DNAUC (mg h/mL/mg/kg)
14
5.4
4.5
12
16
390
18
5.1
4.7
11
30
850
5.5
4.9
11
7.6
8.5
13
100
160
Clearance (Cl) and volume of distribution (Vdss) were calculated following a 1 mg/kg
iv dose. Half life (T1/2), oral bioavailability (F), and dose-normalized area under the
curve (DNAUC) (mg h/mL/mg/kg) were calculated following solution doses of 3 mg/
kg.
Acknowledgments
very promising conformationally restricted alternative scaffold to
the bicyclic tetrahydroquinoline.
The authors wish to thank David McCoy, Richard Hazen and
Wendell Lawrence for providing HIV-1 data, as well as Amanda
G. Culp, Rachel M. Robeson, and Manon Villeneuve for chiral reso-
lutions. We additionally wish to acknowledge Jeanette A. Krause
(University of Cincininati) for crystallographic determination of
14a, as well as funding for the SMART6000 diffractometer through
NSF-MRI Grant CHE-0215950 (University of Cincinnati).
Based on promising anti-HIV activity, the octahydrophenanthr-
oline derivative 14a was chosen for further studies (Table 2). Com-
pound 14a showed a good overall pharmacokinetic profile in rat
and dog, and showed a general improvement over the tetrahydro-
quinoline analog 2a. Clearance of 14a was lower in both rat and
dog with moderate improvements in half-life over 2a. Oral bio-
availability of 14a was also improved compared to 2a in both spe-
cies, as was overall oral exposure as indicated by the dose-
normalized AUCs (DNAUCs), which were nearly fourfold higher
for 14a in the rat and greater than fivefold higher than 2a in the
dog.
References and notes
1. Berson, J. F.; Long, D.; Doranz, B. J.; Rucker, J.; Jirik, F. R.; Doms, R. W. J. Virol.
1996, 70, 6288.
2. Cashen, F. A.; Nervi, B.; DiPersio, J. Future Oncol. 2007, 3, 19.
3. Shaheen, F.; Collman, R. G. Curr. Opin. Infect. Dis. 2004, 17, 7.
4. Yang, O. O.; Swanberg, S. L.; Lu, Z.; Dziejman, M.; McCoy, J.; Luster, A. D.;
Walker, B. D.; Herrmann, S. H. J. Virol. 1999, 73, 4582.
In conclusion, the tricyclic (4aR,10bS)-1,2,3,4,4a,5,6,10b-octahy-
dro-1,10-phenanthroline scaffold was found to be a good alternative

2190
J. G. Catalano et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2186–2190
5. Crump, M. P.; Gong, J. H.; Loetscher, P.; Rajarathnam, K.; Amara, A.; Arenzana-
Seisdedos, F.; Virelizier, J. L.; Baggiolini, M.; Sykes, B. D.; Clark-Lewis, I. EMBO J.
1997, 16, 6996.
6. Ichiyama, K.; Yokoyama-Kumakura, S.; Tanaka, Y.; Tanaka, R.; Hirose, K.;
Bannai, K.; Edamatsu, T.; Yanaka, M.; Niitani, Y.; Miyano-Kurosaki, N.; Takaku,
H.; Koyanagi, Y.; Yamamoto, N. Proc. Natl. Acad. Sci. U.S.A. 2003, 100, 4185.
7. De Clercq, E. Nat. Rev. Drug Disc. 2003, 2, 581.
8. (a) Bridger, G.; Skerlj, R.; Kaller, A.; Harwig, C.; Bogucki, D.; Wilson, T. R.;
Crawford, J.; McEachern, E. J.; Atsma, B.; Nan, S.; Zhou, Y.; Schols, D.; Smith, C. D.;
DiFluri, R. M. WO patent 2003/055876; (b) Crawford, J. B.; Zhu, Y.; Chen, G.; Baird,
I. R.; Skerlj, R. WO patent 2006/039250; (c) Crawford, J. B.; Chen, G.; Gauthier, D.;
Wilson, T.; Carpenter, B.; Baird, I. R.; McEachern, E.; Kaller, A.; Harwig, C.; Atsma,
B.; Skerlj, R. T.; Bridger, G. J. Org. Process Res. Dev. 2008, 12, 823.
16. Absolute configurations by ab initio vibrational circular dichroism (VCD) were
assigned as follows. Experimental VCD spectra were acquired for samples in
chloroform (approx. 10 mg/125 L) using BioTools ChiralIR FT-VCD
spectrometer operating at 4 cmÀ1 resolution between 2000 and 800 cmÀ1
D
-
l
a
.
Model VCD and IR spectra were simulated at the quantum mechanical level
using the GAUSSIAN 03 software suite. Stereochemical assignments were made by
comparing baseline-corrected experimental VCD spectra with VCD spectra
calculated for corresponding models.
17. (a) GAUSSIAN 03; Gaussian: Pittsburgh, PA, USA (www.gaussian.com/index.htm);
(b) Minick, D. J.; Rutkowske, R. D.; Miller, L. A. D. Am. Pharm. Rev. 2007, 10, 118;
(c) Freedman, T. B.; Cao, X.; Dukor, R. K.; Nafie, L. A. Chirality 2003, 15, 743; (d)
Stephens, P. J.; Devlin, F. J.; Pan, J.-J. Chirality 2008, 20, 643.
18. Knupp, G.; Frahm, A. W. Chemishe Berichte 1984, 117, 2076.
9. Gudmundsson, K. S.; Sebahar, P. R.; Richardson, L. D.; Miller, J. F.; Turner, E. M.;
Catalano, J. G.; Spaltenstein, A.; Lawrence, W.; Thomson, M.; Jenkinson, S.
Bioorg. Med. Chem. Lett. 2009, 19, 5048.
10. Gudmundsson, K. S.; Boggs, S. D.; Catalano, J. G.; Svolto, A.; Spaltenstein, A.;
Thomson, M.; Wheelan, P.; Jenkinson, S. Bioorg. Med. Chem. Lett. 2009, 19, 6399.
11. Abbiati, G.; Arcadi, A.; Bianchi, G.; Fiuseppe, S.; Marinelli, F.; Rossi, E. J. Org.
Chem. 2003, 68, 6959.
19. 2,6-difluoropyridine (31.5 mL, 0.348 mol) was diluted with 30% ammonium
hydroxide (200 mL) in a steel bomb and heated to 110 °C overnight. The bomb
was cooled to room temperature over 2 h then further cooled to 0 °C for 2 h.
The resulting solid was filtered and rinsed with water to obtain 26.39 g as a
white solid. The filtrate was extracted with dichloromethane, dried over
sodium sulfate and concentrated to afford an additional 9.3 g (92% overall
yield) of 6-fluoro-2-pyridinamine. A portion of the solid (5 g, 0.044 mol) was
dissolved in 1,2-dichloroethane (20 mL) and 1,3-dichloro-2-propanone
(34.2 mL, 4.34 mol) was added in two portions. The reaction was stirred at
40 °C over 2 days. The resulting solid was collected by filtration, dissolved in
absolute ethanol (100 mL), and refluxed at 90 °C overnight. The solvent was
evaporated and dichloromethane added to the residue followed by saturated
aqueous sodium bicarbonate. The mixture was added to a separatory funnel
and the phases separated. The aqueous layer was extracted two additional
times with dichloromethane and once with a 3:1 chloroform:isopropanol
mixture. The combined organic layers were dried over sodium sulfate and
concentrated to give 3.61 g (62%) of 2-(chloromethyl)-5-fluoroimidazo[1,2-
a]pyridine as a black oil, which solidified upon standing. 1H NMR (400 MHz,
DMSO-d6) d 5.02 (s, 2H), 7.29 (d, 1H), 7.74 (d, 1H), 7.88 (m, 1H), 8.41 (s, 1H);
MS m/z 185 (M+1).
12.
A mixture of 1,2-cyclohexanedione (43.6 g, 389 mmol), propargylamine
(26.8 mL, 389 mmol), and sodium tetrachloroaurate dihydrate (4.9 g,
11.7 mmol) in ethanol (800 mL) was heated at 75 °C for 16 h. The mixture
was filtered and the filtrate concentrated. The residue was slurried with ethyl
acetate for 30 min and filtered through a silica gel plug with additional ethyl
acetate. The filtrate was concentrated and the residue slurried in diethyl ether.
The precipitate was collected by filtration and dried under vacuum to give 6,7-
dihydro-8(5H)-quinolinone (13.3 g, 23% yield).
13. (a) McEachern, E. J.; Yang, W.; Chen, G.; Skerlj, R. T.; Bridger, G. J. Synth.
Commun. 2003, 33, 3497; (b) Kelly, T. R.; Lebedev, R. L. J. Org. Chem. 2002, 67,
2197; (c) Lemke, T. L.; Shek, T. W.; Cates, L. A.; Smith, L. K. J. Med. Chem. 1997,
20, 1351.
14. An, H.; Wang, T.; Mohan, V.; Griffey, R. H.; Cook, P. D. Tetrahedron 1998, 54, 3999.
15. Separation was performed on ChiralPak ADH column (250 Â 10 mm id, 5
l
m;
20. 1H NMR (400 MHz, methanol-d4) d ppm 1.7 (m, 5H), 2.1 (m, 1H), 2.4 (m, 5H),
2.7 (m, 5H), 3.0 (m, 1H), 3.1 (m, 5H), 3.6 (m, 1H), 3.6 (d, J = 14.6 Hz, 1H), 4.0 (d,
J = 14.5 Hz, 1H), 6.4 (d, J = 7.3 Hz, 1H), 7.2 (m, 3H), 7.5 (d, J = 9.1 Hz, 1H), 7.6 (s,
1H), 8.3 (d, J = 6.4 Hz, 1H); MS m/z 417 (M+1).
ChiralTechnologies, West Chester, PA) under supercritical conditions maintained
at 40 °C, 140 bar, with methanol, containing 0.5% DEA (diethylamine), modified
CO2 (30% MeOH, 70% CO2) delivered at a combined flow rate of 10 mL/min on a
Thar Discovery Series SFC system (Thar Instruments, Inc.; Pittsburgh, PA). The
geoisomers were monitored using a Gilson selectable wavelength 151 UV–vis
detector at 230 nm.
21. The following crystal structure has been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition number CCDC
760486.