A concise synthesis of HIV integrase inhibitors bearing the dipyridone acid motif

Article abstract of DOI:10.1016/j.tetlet.2010.11.112

An efficient route to dipyridone acid HIV integrase inhibitors is developed. The key steps include a one-pot three-step formation of the core template (containing one point of structural diversity) followed by a regioselective benzylation and in situ depr

Full text of DOI:10.1016/j.tetlet.2010.11.112

Tetrahedron Letters 52 (2011) 512–514
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A concise synthesis of HIV integrase inhibitors bearing the dipyridone acid motif
⇑
Michelle Y. Platts , Christopher G. Barber, Jean-Yves Chiva, Rachel L. Eastwood, David R. Fenwick,
Kerry A. Paradowski, David C. Blakemore
Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 July 2010
Revised 9 November 2010
Accepted 19 November 2010
Available online 24 November 2010
An efficient route to dipyridone acid HIV integrase inhibitors is developed. The key steps include a one-
pot three-step formation of the core template (containing one point of structural diversity) followed by a
regioselective benzylation and in situ deprotection to afford the title compounds.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Dipyridone acid
Integrase
Heterocycles
Antiviral agents
Ring-closure
In connection with a programme to discover novel HIV integr-
ase inhibitors,1 we report our successful exploits in the preparation
of 6-benzyl-1-alkyl-4,7-dioxo-1,4,6,7-tetrahydro-1,6-naphthyri-
dine-3-carboxylic acids (dipyridone acids) 1, Figure 1. From the
outset, we desired a facile and reliable method for the preparation
of dipyridone acids 1, which would allow rapid access to a range of
analogues in order to study the structure–activity relationships
(SARs) in this series.
Our retrosynthetic analysis (Scheme 1) reveals that 1 may be
derived from the hydrolysis and alkylation of pyridine ester 2.
The bromo analogue of 2 (X = Br, R = CH2CH3) has been previously
reported by Strehlke and was synthesised in nine steps from 2-
amino-5-methylpyridine.2 We required a more concise route to
2, which we believed could be formed from the addition of a suit-
able amine to ethyl (2E/Z)-2-[(4,6-dichloropyridin-3-yl)carbonyl]-
3-(dimethylamino)prop-2-enoate (3), followed by ring-closure
onto the chloropyridine moiety. Compound 3 should be accessible
from 4,6-dichloronicotinic-3-carboxylic acid (4), which can be pre-
pared from diethyl 1,3-acetonedicarboxylate (5).
As outlined in Scheme 2, acid 4 was synthesised in three-steps
from commercially available 1,3-acetonedicarboxylate 5. Reaction
of 5 with triethyl orthoformate in acetic anhydride, followed by
cyclisation with aqueous ammonia, gave 6.3 Treatment of 6 with
phosphorus oxychloride under reflux conditions followed by ester
hydrolysis under basic conditions gave the desired acid 4.4 Com-
pound 4 was readily converted into the acid chloride 75 and was
subsequently treated with ethyl 3-dimethylaminoacrylate, using
the conditions developed by Shinkai and co-workers,6 to provide
enaminoate 3. Enaminoate 3 reacted readily with a series of
amines. In this example it reacts with L-(+)-valinol to provide 8,
and after cyclisation under basic conditions, afforded ketoester 9
in moderate yield. This step was unoptimised, but allowed access
to sufficient material to provide key analogues for our SAR analysis.
We then attempted chloropyridine–ketoester hydrolysis to the
corresponding pyridone acids directly. We anticipated that hydro-
lysis of intermediate 10, for example (prepared from 2,4-dime-
thoxybenzylamine using the route outlined in Scheme 2), using
sodium hydroxide would be straightforward. However, initial work
suggested that this reaction was far from trivial and a range of both
acidic and basic hydrolysis conditions met with little success; our
most successful attempt to form a pyridone acid utilised potassium
tert-butoxide in t-butanol, which converted ketoester 10 into the
desired compound 11, albeit in poor isolated yield (Scheme 3).
As expected, in the presence of sodium hydroxide it appeared
that the initial ester hydrolysis was facile (by LCMS) while dis-
placement of the chloro substituent was hampered due to the poor
solubility of the intermediate chlorocarboxylates in the reaction
solvents used (water, DMSO and DMF). This led us to investigate
O
O
R1
N
OH
where R=alkyl
O
N
R
R1=halide(s)
1
⇑
Corresponding author. Tel.: +44 130 464 9141; fax: +44 130 465 1821.
E-mail address: michelle.platts@pfizer.com (M.Y. Platts).
Figure 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.112

M. Y. Platts et al. / Tetrahedron Letters 52 (2011) 512–514
513
O
O
O
O
O
O
N
R1
N
OH
OEt
N
OEt
N
Cl
O
N
R
N
R
X
Cl
3
1
2
X=Cl
O
O
O
O
N
OH
OEt
EtO
Cl
Cl
5
4
Scheme 1. Retrosynthesis of compounds of type 1.
O
O
O
O
O
O
a
b
c
N
OEt
N
N
OH
Cl
EtO
OEt
HO
OH
Cl
Cl
Cl
Cl
5
6
7
4
O
O
N
O
O
O
O
N
e
d
N
OEt
f
OEt
N
N
OEt
Cl
Cl
Cl
N
Cl
Cl
OH
OH
3
9
8
Scheme 2. Reagents and conditions: (a) CH(OEt)3, Ac2O, 145 °C then aq NH3 61%; (b) (i) POCl3, reflux 73%; (ii) LiOH, H2O, THF, rt 96%; (c) SOCl2, DMF, toluene, reflux,
quantitative; (d) ethyl 3-dimethylaminoacrylate, Et3N, THF, 65 °C, 79%; (e)
L
-(+)-valinol, THF, rt 78%; (f) K2CO3, DMF, 100 °C, 35%.
NH2
O
N
O
17
alcohol solvent systems for the hydrolysis. The use of hydroxide in
methanol showed evidence for the formation of the corresponding
methoxypyridine, and it was found that the formation of methoxy-
pyridine 12 from the reaction of 9 with sodium methoxide in
methanol occurred readily and in high yield (Scheme 4). With 12
in hand, the desired product 16 was now accessible. Demethyla-
tion with TMSI in CH2Cl2 gave pyridone 13, and when treated with
14 under basic conditions, led to a mixture of N- and O-benzylated
pyridone products (ꢀ1:1), as well as benzylation of the carboxylic
acid. Separation of the desired N-benzyl isomer 15 followed by es-
O
O
N
N
OH
N
OEt
OH
O
Cl
Cl
OH
a
3
18
Scheme 5. Reagents and conditions: (a) 17, NaOMe, MeOH, reflux then aqueous
work-up, 70%.
F
Cl
O
N
O
O
O
N
O
O
Br
O
N
O
F
O
N
O
14
N
a
OEt
HN
OH
Cl
N
OH
N
OH
Cl
O
O
a
O
OH
OH
11
10
O
O
19
Scheme 6. Reagents and conditions: 14, NaI, MeCN, MW, 170 °C, 1 h, 57%.
18
Scheme 3. Reagents and conditions: (a) KOtBu, t-BuOH, 90 °C, 10–15%.
O
O
O
O
O
O
a
b
OEt
N
OH
N
OH
HN
Cl
N
O
N
O
N
OH
OH
OH
9
12
13
F
Cl
Br
Cl
F
O
O
F
F
O
O
14
Cl
Cl
d
OH
N
O
N
c
O
N
O
N
OH
OH
16
15
Scheme 4. Reagents and conditions: (a) NaOMe, MeOH, reflux, then aqueous work-up, 85%; (b)TMSI, CH2Cl2, rt, 65%; (c) 14, K2CO3, DMF, 60 °C, 28%; (d) 1 N NaOH(aq), THF, rt, 60%.

514
M. Y. Platts et al. / Tetrahedron Letters 52 (2011) 512–514
O
O
R1
F
Cl
R1=
N
OH
Cl
Cl
when R=
OH
N
R
O
F
Cl
1
F
F
F
Cl
OH
when R1=
HO
R=
OH
OH
Figure 2.
ter hydrolysis afforded dipyridone acid 16 in reasonable yield. Gi-
ven the difficult isolation of intermediate 13 and the subsequent
low yielding unselective alkylation we decided to investigate a
more direct and selective route to compounds of type 1, since
the synthetic complexity of the existing route precluded an effi-
cient elaboration of the SAR.
work has been the reduction of the route complexity as a means
to explore rapidly the SAR.
References and notes
1. Semenova, E. A.; Marchand, C.; Pommier, Y. Adv. Pharmacol. 2008, 56, 199.
2. Strehlke, P. Eur. J. Med. Chem. 1977, 12, 541.
The first improvement made to the route was to telescope the
three-steps of amine addition, ring-closure and chloro to methoxy
conversion into a single step. This was achieved by reacting enami-
noate 3 with the desired amine, in this case 17, in the presence of
sodium methoxide in methanol at reflux, to afford the correspond-
ing product 18 in an impressive overall yield, (Scheme 5). The abil-
ity to utilise the methoxide as base and nucleophile in such a
sequence is, to our knowledge, unprecedented.
3. Den Hertog Recl. Trav. Chim. Pays-Bas Belg. 1946, 65, 129.
4. Wallace, E.; Hurley, B.; Yang, H. W.; Lyssikatos, J.; Blake, J. U.S. Patent 049419,
2005; Chem. Abstr. 2005, 142, 298094.
5. Fucini, R. V.; Hanan, E. J.; Romanowski, M. J.; Elling, R. A.; Lew, W.; Barr, K. J.;
Zhu, J.; Yoburn, J. C.; Liu, Y.; Fahr, B. T.; Fan, J.; Lu, Y.; Pham, P.; Choong, I. C.;
VanderPorten, E. C.; Bui, M.; Purkey, H. E.; Evanchik, M. J.; Yang, W. Bioorg. Med.
Chem. Lett. 2008, 18, 5648.
6. Sato, M.; Motomura, T.; Aramaki, H.; Matsuda, T.; Yamashita, M.; Ito, Y.;
Kawakami, H.; Matsuzaki, Y.; Watanabe, W.; Yamataka, K.; Ikeda, S.; Kodama,
E.; Matsuoka, M.; Shinkai, H. J. Med. Chem. 2006, 49, 1506.
7. Preparation of 18.
We then explored a further improvement to the route which in-
volved direct benzylation of the methoxypyridine intermediate
18.7 It was anticipated that benzylation would occur selectively
on the pyridine nitrogen and that the resulting quaternary ammo-
nium salt would be readily demethylated using an appropriate
nucleophile. Under the conditions reported by Bowman and Bridge,
who had shown a similar reaction with 2-methoxypyridine to be
successful,8 we attempted the regioselective synthesis of N-benzyl
pyridone 19. Our initial results in refluxing MeCN showed no reac-
tion, although pleasingly, at the higher temperature achieved un-
der microwave conditions, the desired reaction did occur,
indicating that the pyridine nitrogen in our system was less nucle-
ophilic than that of methoxypyridine (Scheme 6).9 Under these
conditions N-benzylation and demethylation occurred exclusively
to afford dipyridone acid 19.10
Similar methodology was applied to prepare further analogues
of compound 19 (Fig. 2). These derivatives possessed potent anti-
HIV integrase activity and a further explanation of the SAR will
be described elsewhere.
In summary, a novel and concise synthetic route to dipyridone
acids of type 1 has been achieved. Significant improvements made
to the initial route made for a highly efficient synthesis of cyclised
methoxypyridine intermediates and regioselective N-benzyl
dipyridone acid preparation. Late stage N-benzyl variation has al-
lowed rapid access to a range of analogues. A key feature of this
To a stirred suspension of 3 (100 mg, 0.32 mmol) in MeOH (10 mL) was added
17 (41 mg, 0.35 mmol) and the mixture was stirred at rt for 1 h. NaOMe
(170 mg, 3.15 mmol) was added portionwise and the mixture was stirred at
reflux for 4 h. The resulting mixture was concentrated under reduced pressure
and diluted and acidified to pH 1 with 2 N HCl (aq). The aqueous was extracted
with 5% MeOH and CH2Cl2 (15 mL) and the organics dried (Na2SO4), filtered and
concentrated under reduced pressure. The crude product was purified by
chromatography (silica gel, eluting with 100% heptane–100% EtOAc) to provide
18 as a white foam (71 mg, 70% yield). 1H NMR (400 MHz, CDCl3): d = 9.34 (1H,
s), 8.82 (1H, s), 6.79 (1H, s), 4.34 (1H, m), 4.17–4.05 (5H, m), 2.19 (1H, m), 1.24
(1H, m), 1.13 (3H, d, J = 6.6 Hz), 1.03 (1H, m), 0.82 (3H, t, J = 7.4 Hz). LRMS (CIÀ):
319 [MÀH]À.
8. Bowman, W. R.; Bridge, C. F. Synth. Commun. 1999, 29, 4051.
9. For an example of microwave-assisted 2-methoxypyridine quaternisation and
MeO-group deprotection in one-pot, see: Tielmann, P.; Hoenke, C. Tetrahedron
Lett. 2006, 47, 261.
10. Preparation of 19.
To a stirred suspension of 18 (71 mg, 0.22 mmol) in MeCN (1 mL) was added 14
(109 mg, 0.49 mmol) and NaI (66 mg, 0.44 mmol) and the mixture was heated
under microwave irradiation (Biotage, Initiator 8) at 170 °C for 1 h. The
resulting mixture was concentrated under reduced pressure, dissolved in
CH2Cl2 (5 mL), washed with 10% aqueous Na2S2O3 solution (5 mL), dried
(Na2SO4), filtered and concentrated under reduced pressure. The crude product
was purified by reverse phase HPLC (MeCN/H2O/TFA 5%/95%/0.1%, flow rate
20 mL/min, column: Phenomenex C18 100A 150 Â 15 mm, 10 micron) to
provide 19 as a yellow solid (57 mg, 57% yield). 1H NMR (400 MHz, DMSO-d6):
d = 9.15 (1H, s), 8.67 (1H, s), 7.54 (1H, dt, J = 7.36, 2.32 Hz), 7.26–7.17 (2H, m),
6.78 (1H, s), 5.43 (2H, s), 5.15 (1H, t, J = 5.13 Hz), 4.45 (1H, m), 3.84 (1H, m),
3.65 (1H, m), 2.07 (1H, m), 1.24 (1H, m), 1.04 (3H, d, J = 6.50 Hz), 1.03 (1H, m),
0.77 (3H, t, J = 7.40 Hz). LRMS (CI+): 449/451 [M+H]+.