The synthesis of tetrahydropyridopyrimidones as a new scaffold for HIV-1 integrase inhibitors

Article abstract of DOI:10.1016/j.tetlet.2007.07.043

An efficient synthesis of methyl 9-amino-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate as a late stage intermediate for a new class of HIV-1 integrase inhibitors is described. After construction of the bicyclic core scaffold,

Full text of DOI:10.1016/j.tetlet.2007.07.043

Tetrahedron Letters 48 (2007) 6552–6555
The synthesis of tetrahydropyridopyrimidones as a
new scaffold for HIV-1 integrase inhibitors
Olaf D. Kinzel,* Edith Monteagudo, Ester Muraglia, Federica Orvieto,
Giovanna Pescatore, Maria del Rosario Rico Ferreira,
Michael Rowley and Vincenzo Summa
Departments of Medicinal Chemistry and Drug Metabolism, IRBM-MRL Rome, Via Pontina, Km 30.600,
00040 Pomezia, Rome, Italy
Received 3 April 2007; revised 28 June 2007; accepted 6 July 2007
Available online 12 July 2007
Abstract—An efficient synthesis of methyl 9-amino-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate
as a late stage intermediate for a new class of HIV-1 integrase inhibitors is described. After construction of the bicyclic core scaffold,
a stereoselective introduction of the chiral amino group in the 9-position is achieved.
Ó 2007 Elsevier Ltd. All rights reserved.
We have previously reported on N-methyl-5-hydroxy-
pyrimidone carboxamides as potent HIV-1 integrase
inhibitors, of which compound A (Fig. 1) is a represen-
tative example.1 During the SAR exploration of these
inhibitors, one of our efforts concentrated on fused bicy-
clic analogs B shown in Figure 1. Herein we report on
the synthesis of tetrahydropyridopyrimidone C (Fig. 2)
as a versatile precursor for HIV-1 integrase inhibitors
of type B.2
3,4-dihydroxy-pyrimidines can be obtained by two
methods: either by a condensation reaction between
amidines and dihydroxyfumarate derivatives 33 or by a
reaction of amidoximes with dimethylacetylene dicarb-
oxylate (DMAD).4
Cyclic amidines 2 (Route 1, Fig. 2) or cyclic amidoxime
4 (Route 2, Fig. 2) seemed attractive starting materials
to us because of the convergent formation of the tetra-
hydropyridopyrimidone bicycle in one step. The use of
these cyclic analogs was unprecedented though and the
feasibility of both routes had to be explored. Route 1
(Scheme 1) started with the synthesis of the benzyl pro-
tected dimethyldihydroxyfumarate 3a by a Claisen con-
densation of methyl benzyloxyacetate and dimethyl
oxalate as described previously.3 The crude material 3a
Our retrosynthetic analysis for C is shown in Figure 2.
We envisioned the installation of the chiral methylamino
group in the 9-position after the formation of the core
scaffold in order to avoid racemization during the cycli-
zation step which occurs at elevated temperatures or in
the presence of a strong base. In general, 2-carboxy-
O
O
OH
F
Me
(+/-)
OH
F
N
N
H
H
N
N
N
N
N
O
N
O
R
Me
Me
A
B
Figure 1.
Keywords: Tetrahydropyridopyrimidone; Integrase inhibitor; 1,2,4-Oxadiazoline; Amidoxime.
*
Corresponding author. Tel.: +39 06 91093334; fax: +39 06 91093654; e-mail: olaf_kinzel@merck.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.043

O. D. Kinzel et al. / Tetrahedron Letters 48 (2007) 6552–6555
MeO2C
6553
OBn
N
Route 1
+
HO
CO2R1
R1= Me, tBu
O
N
NH2
O
N
OP
OH
2
3
N
N
CO2Me
CO2Me
CO2Me
CO2Me
OH
NH
HN
C
N
Me
+
Route 2
4
Figure 2.
MeO2C
OBn
(CO2Me)2
LDA/THF, -78°C
Route 1
O
N
CO2Me
DBU/
OR2
CO2Me
MeOH, 50°C
Pd(C)/H2
N
OH
N
+
BnO
NH2
CO2Me
2
3a
1a R2= Bn
1 R2= H
20%; 3 steps
Scheme 1.
1. NaH, NaI,
Pd(C)/H2
MeOH
NH(Boc)OBn, DMF
2. HCl/1,4-dioxane
CO2Me
OH
OBn
N
N
+
Cl
CN
NH2+ Cl-
NH2+ Cl-
4
86%
98%
CO2Me
4a
4
Route 2
Et3N, CHCl3
83%
O
MeO2C
o
-xylene,
OR3
CO2Me
reflux
O
N
N
CO2Me
N
42%
N
1 R3 = H
1b R3 = Bz
5
Py, Bz2O
77%
Scheme 2.
was employed in a condensation reaction with the com-
mercially available cyclic amidine 2, using DBU as base
in methanol at 50 °C. After cleavage of the benzyl ether
by hydrogenation, tetrahydropyridopyrimidone 1 was
obtained in a 20% yield. To explore the alternative
Route 2 (Scheme 2), the cyclic amidoxime 4 had first
to be prepared. This was achieved efficiently in a three
step sequence by alkylation of N-Boc-O-benzyl hydro-
xylamine with 4-chlorovaleronitrile,5 then treated with
4 M HCl in 1,4-dioxane which promoted Boc-cleavage
and a subsequent in situ cyclization to 4a. Finally, cleav-
age of the benzyl ether by hydrogenation afforded 4 in
high yield. 1-Hydroxypiperidin-2-iminium chloride 4
readily reacted with DMAD in chloroform in the pres-
ence of one equivalent of base. The formed adduct
was determined as the bicyclic 1,2,4-oxadiazoline 5.6
Heating to reflux in o-xylene for 5 h promoted ring-
opening and subsequent thermal rearrangement/cycliza-
tion to tetrahydropyridopyrimidone 1 which was iso-
lated in 42% yield. The 3-hydroxyl group of 1 was
protected as a benzoic ester in order to increase the sol-
ubility in non-protic solvents. Route 2 was used for the
preparation of multigram quantities of intermediate 1b.
Next, the installation of the amino group in position 9
had to be accomplished, ideally in an enantioselective
fashion. Our first intent to prepare the 9-oxo-analog
1c as an useful intermediate for an enantioselective syn-
thesis was hampered by the difficulty to cleanly oxidize
1b (Scheme 3). Reagents like PDC, PCC, CrO3, MnO2
or KMnO4 gave either low conversion or degradation.
An alternative approach was found by bromination of
1b with NBS under radical conditions as described pre-
viously.1 The resulting bromo-intermediate 6 was

6554
O. D. Kinzel et al. / Tetrahedron Letters 48 (2007) 6552–6555
O
O
N
O
NBS, CCl4
S-(-)-1-phenyl-
OH
OH
(Bz)2O2, 75°C
OBz
ethylamine (4eq.)
+
N
N
N
1b
70%
N
CO2Me
CO2Me
N
CO2Me
NH
Me
NH
Me
Br
6
7b
O
N
7a
OBz
CO2Me
Ox.
O
N
conditions
ratio 7a : 7b
O
N
N
THF, 25°C
DMF, 25°C
50 : 50
44 : 56
42 : 58
36 : 64
32 : 68
30 : 70
26 : 74
O
1c
CO2Me
DMSO, 25°C
MeOH, 25°C
MeOH-H2O, 7:3, 25°C
MeOH-H2O, 1:1, 25°C
D
MeOH-H2O, 7:3, -30-> 25°C
Scheme 3.
subjected to a reaction with (S)-(À)-1-phenylethylamine
in DMF to give a pair of diastereomeric amines 7a and
7b. Interestingly, this reaction proceeded with a slight
diasteromeric excess (44:56, Scheme 3) and screening
for conditions to further increase the diastereoselectivity
was undertaken. The best result (48% de) was obtained
when the reaction was carried out in a MeOH–water
mixture (7:3) at À30 °C with an excess of the chiral
amine (Scheme 3). Polar protic solvents and low temper-
atures increased the diastereoselectivity. We believe that
the first step in the reaction of 6 with (S)-(À)-1-phenyl-
ethylamine is O-deprotection, since products containing
the benzoic ester were never observed. In the presence of
an excess of amine HBr can eliminate to form a reactive
p-quinone-like structure D as an achiral intermediate
(Scheme 3). After methylation of the amino group the
separation of the two diastereomers 8a and 8b was per-
formed by preparative RP-HPLC. The final step was the
cleavage of the chiral auxiliary by catalytic hydrogena-
tion. Using this procedure the versatile intermediate C
could be prepared in 53% yield from racemic 6 (Scheme
4).
Since the separation of 8a and 8b by RP-HPLC was time
consuming, an alternative procedure for the separation
of the diastereomers either by crystallization or by chro-
matography on silica gel was sought. Attempts to enrich
the mixture of diastereomers by crystallization were
unsuccessful and our attention turned to a separation
by silica gel chromatography. For this purpose the ami-
no and the hydroxyl group had to be protected with
groups whose removal should proceed without loss of
enantiomeric purity. After several attempts to protect
the amino group of 7a/7b as amides or carbamates,
the route shown in Scheme 5 was found to be a practical
solution. After the diastereoselective reaction of 6 with
the chiral amine the intermediate was formylated on
the secondary amine and acetylated on the hydroxy
group (the corresponding formic ester was labile
towards hydrolysis). The obtained mixture of diastereo-
1. S-(-)-1-phenyl-
ethylamine,
MeOH/H2O (7:3); -30°C to rt
2. H2CO, NaBH3CN, MeOH
O
N
O
OH
Pd(C)/H2,
OH
N
3. separation of diast. on
prep. RP-HPLC
MeOH
93%
N
CO2Me
6
-
N
CO2Me
CF3CO2
57%
N
H+
+ CF3CO2
-
Me
NH2
8b
Me
Me
C
> 99% de
Scheme 4.
1. R-(+)-1-phenyl-
ethylamine,
MeOH/H2O; -30 to rt
2. HCO2H, (Ac)2O, TEA
3. (Ac)2O, TEA, DMAP
4. separation of dia-
stereomers on SiO2
O
O
N
OAc
OAc
N
BH3-SMe2,
THF, 0-45°C
N
O
CO2Me
N
CO2Me
6
97%
N
28%
N
Me
9
10
Scheme 5.

O. D. Kinzel et al. / Tetrahedron Letters 48 (2007) 6552–6555
6555
1. R-(+)-1-phenyl-
ethylamine,
O
N
O
N
MeOH/H2O; -30°C to rt
2. separation of diast. on
prep. RP-HPLC
OH
OH
N
N
Pd(C)/H2
MeOH
CO2Me
CO2Me
6
-
+
-
60%
+
55%
CF3CO2
NH3
CF3CO2
NH2
12
11
O
N
OH
N
13
(S)-MTPA,
CO2Me
MeO CF3
EDC, HOBt,
DIPEA, DMF
NH
12
12
(S)
O
81%
O
OH
N
14
(R)-MTPA,
N
CO2Me
EDC, HOBt,
F3C OMe
NH
DIPEA, DMF
(R)
O
50%
Scheme 6.
mers separated well by silica gel chromatography and a
subsequent reduction of the formamide to a methyl
amine by borane–dimethylsulfide furnished intermediate
10 without loss of enantiomeric purity. The absolute
configuration of 12 (Scheme 6, using R-(+)-1-phenyleth-
ylamine) was determined by derivatization with the two
enantiomers of the chiral reagent MTPA and compari-
son of the chemical shifts of the resulting diastereomers.
Energy assessment on the MTPA amides using molecu-
lar mechanics and semiempirical (AM1) calculations,
together with careful examination of aromatic shielding
and deshielding effects on the substituents in position a
to the amine, indicated a configuration of S at the
chiral center in 12.7
References and notes
1. Summa, V.; Petrocchi, A.; Matassa, V. G.; Gardelli, C.;
Muraglia, E.; Rowley, M.; Gonzalez Paz, O.; Laufer, R.;
Monteagudo, E.; Pace, P. J. Med. Chem. 2006, 49, 6646–
6649.
2. (a) Crescenzi, B.; Kinzel, O.; Muraglia, E.; Orvieto, F.;
Pescatore, G.; Rowley, M.; Summa, V. A preparation of
tetrahydro-4H-pyrido[1,2-a]pyrimidine derivatives, useful
as HIV integrase inhibitors. WO 2004058757 A1; (b)
Similar bicyclic pyrimidone structures with a heteroatom
in the saturated ring have been described in a recent patent.
Naidu, B. N.; Banville, J.; Beaulieu, F.; Connolly, T. P.;
Krystal, M. R.; Matiskella, J. D.; Ouellet, C.; Plamondon,
S.; Remillard, R.; Sorenson, M. E.; Ueda, Y.; Walker, M.
A. Bicyclic heterocycles as HIV integrase inhibitors. WO
2007064316 A1.
In summary, an efficient synthesis of the new hetero-
cyclic ring system methyl 3-hydroxy-4-oxo-6,7,8,9-tetra-
3. Dreher, S. D.; Ikemoto, N.; Gresham, V.; Liu, J.; Dormer,
P. G.; Balsells, J.; Mathre, D.; Novak, T. J.; Armstrong, J.
D., III. Tetrahedron Lett. 2004, 45, 6023–6025.
hydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate
has
been achieved. The installation of a chiral amino group
in the 9-position has been performed after the cycliza-
tion step in a stereoselective fashion using a racemic bro-
mo-intermediate as starting material.
4. (a) Culbertson, T. P. J. Heterocycl. Chem. 1979, 16, 1423–
1424; (b) Cooper, J.; Irwin, W. J. J. Chem. Soc. Perkin
Trans. 1 1976, 2038–2045; (c) Summa, V.; Petrocchi, A.;
Matassa, V. G.; Taliani, M.; Laufer, R.; De Francesco, R.;
Altamura, S.; Pace, P. J. Med. Chem. 2004, 47, 5336–5339;
(d) Stansfield, I.; Avolio, S.; Colarusso, S.; Gennari, N.;
Narjes, F.; Pacini, B.; Ponzi, S.; Harper, S. Bioorg. Med.
Chem. Lett. 2004, 14, 5085–5088; (d) Koch, U.; Attenni, B.;
Malancona, S.; Colarusso, S.; Conte, I.; Di Filippo, M.;
Harper, S.; Pacini, B.; Giomini, C.; Thomas, S.; Incitti, I.;
Tomei, L.; De Francesco, R.; Altamura, S.; Matassa, V. G.;
Narjes, F. J. Med. Chem. 2006, 49, 1693–1707; (e) Zhong,
Y.-L.; Zhou, H.; Gauthier, D. R., Jr.; Askin, D. Tetrahe-
dron Lett. 2006, 47, 1315–1317.
Acknowledgements
The authors wish to thank Silvia Pesci for the assign-
ment of NMR spectra of compounds 1, 4 and 5 and
Uwe Koch for the conformational analysis of com-
pounds 13 and 14.
5. Bergeron, R. J.; McManis, J. S. Tetrahedron 1989, 45,
4939–4944.
Supplementary data
6. The formation of monocyclic 1,2,4-oxadiazolines has been
described before: Naidu, B. N.; Sorenson, M. E. Org. Lett.
2005, 7, 1391–1393.
Experimental procedures and spectral data of the
products as well as details regarding the determination
of the absolute configuration of 12. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2007.07.043.
´
7. Seco, J. M.; Latypov, S. K.; Quinoa, E.; Riguera, R. J. Org.
˜
Chem. 1997, 62, 7569–7574.