A modular synthesis of novel 4-amino-7,8-dihydro-1,6-naphthyridin-5(6H)- ones as PDE4 inhibitors

Article abstract of DOI:10.1016/j.tetlet.2013.06.016

A versatile, modular synthetic route to a series of 4-amino-7,8-dihydro-1, 6-naphthyridin-5(6H)-ones has been developed. These compounds represent a novel structural class of potent phosphodiesterase IV (PDE4) inhibitors.

Full text of DOI:10.1016/j.tetlet.2013.06.016

Accepted Manuscript
A modular synthesis of novel 4-amino-7,8-dihydro-1,6-naphthyridin-5(6H)-
ones as PDE4 inhibitors
Manel Ferrer, Richard. S. Roberts, Sara Sevilla
PII:
S0040-4039(13)00972-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.06.016
TETL 43069
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
4 March 2013
31 May 2013
5 June 2013
Please cite this article as: Ferrer, M., S. Roberts, Richard., Sevilla, S., A modular synthesis of novel 4-amino-7,8-
dihydro-1,6-naphthyridin-5(6H)-ones as PDE4 inhibitors, Tetrahedron Letters (2013), doi: http://dx.doi.org/
10.1016/j.tetlet.2013.06.016
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A modular synthesis of novel 4-amino-7,8-
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PDE4 inhibitors
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Manel Ferrer, Richard. S. Roberts,* Sara Sevilla

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A modular synthesis of novel 4-amino-7,8-dihydro-1,6-naphthyridin-5(6H)-ones as
PDE4 inhibitors
Manel Ferrer, Richard. S. Roberts,* Sara Sevilla
Almirall S.A., Department of Medicinal Chemistry, Laureano Miró, 408-410, 08980 Sant Feliu de Llobregat, Barcelona, Spain.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A versatile, modular synthetic route to a series of 4-amino-7,8-dihydro-1,6-naphthyridin-5(6H)-
ones has been developed. These compounds represent a novel structural class of potent
phosphodiesterase IV (PDE4) inhibitors.
Available online
Keywords:
PDE4
Inhibitor
Modular synthesis
Tetra-substituted
Dihydronaphthyridinone
Phosphodiesterase IV (PDE4) remains a current target of
interest for anti-inflammatory therapy in respiratory diseases.1
The mixed anti-inflammatory and bronchodilatory effect of
PDE4 inhibitors could allow the discovery of new steroid-
sparing compounds, particularly in the management of asthma
and COPD.
Roflumilast 1 (Daxas®, Daliresp®, Libertek®, Figure 1) is
the first PDE4 inhibitor to be launched on the market, with
several other compounds in advanced stages of clinical trials.2
Many chemically diverse classes of molecules have been
reported as PDE4 inhibitors,3 and the use of X-ray
crystallography has been of particular use to elucidate their
binding modes and to help with the design of more potent
inhibitors.4,5
Figure 2. General structure of 4-amino-7,8-dihydro-1,6-
naphthyridin-5(6H)-ones (NAPs) 2
The heart of the NAP structure is a 4-aminopyridine motif.
Many synthetic methods exist for the synthesis of simple 4-
aminopyridines, however none of the reported methods
provided the specific tetra-substitution pattern we required for
the NAPs.6 In addition, we wanted a versatile method to allow
us to modify the substitution of the groups R1, R2 and R3 and
hence systematically study the structure-activity relationship
(SAR) of each of these positions, either individually or in
combination. Therefore as the central pyridine ring was
common to all structure, we envisaged a convergent synthetic
route, constructing this pyridine each time (Figure 3).
Figure 1. Chemical structure of Roflumilast
As part of our PDE4 program, we were interested in the
synthesis of 4-amino-7,8-dihydro-1,6-naphthyridin-5(6H)-
ones 6 (NAPs, Figure 2) as potential inhibitors.

2
Tetrahedron Letters
Figure 3. Disconnection approach to the NAPs 2
DMSO/THF, 25 ºC, 2h; then NH4OAc (10 equiv), AcOH, 80
ºC, 2h, 8-55%. (e) mCPBA (3 equiv.), CHCl3, 25 ºC, 2h, 67-
100%. (f) Amine R3NH2 5, see text for conditions, 11-76%.
(g) TFA, CHCl3, rt. (h) 7N NH3 in MeOH, 100 ºC
(microwave), 5 h, 87-97% over two steps (i) Aryl bromide
R3Br 19, Pd2(dba)3 (0.1 equiv) Cs2CO3 (1.4 equiv), Xanthphos
(0.2 equiv), dioxane, reflux, 24 h, 14-46%.
The three points of diversity R1, R2 and R3 could then be
sourced from convenient reagent pools: R1 from known
piperidinediones 3,7 themselves derived from β-amino acids,
R2 from ketones and acetophenones 4 and R3 from simple
amines or anilines 5. To complete the central core, we would
also need a tetrapositive carbon atom to which the three units
3, 4, and 5 would be attached. Finally, condensation of
ammonia between the ketone carbonyl of 3 and 4 would
formally close up the aminopyridine of the NAP core (Figure
3).
The diones 9 were synthesised according to reported methods
(Scheme 1).7 Hence, Meldrum’s acid 6 was coupled to the
Boc-protected β-amino acids 7a-c using DCC in a reaction
that was easily scalable to up to 100 g batches without the
need for chromatography. We also included the un-substituted
amino acids Boc-glycine (7d) and Boc-GABA (7e).
Subsequent cyclisation was carried out in refluxing ethyl
acetate. Ring size affected the yield of the newly formed
lactams, with a clear preference for 6 > 5 >> 7, the
unfavourable geometry of closing a 7-membered ring was
such that no reaction took place (Table 1, entry 5). β-
Substitution of the β-amino acid also impeded smooth
cyclisation to some degree (Table 1, entry 3).
Results and Discussion
The overall synthetic route is shown in Scheme 1.
With diones 9a-d in hand we turned to the choice of the
tetrapositive carbon atom synthon (Figure 3). Halides are
ubiquitous synthetic handles in organic chemistry and both
carbon tetrachloride and carbon tetrabromide have been used
to homologate ketones to the corresponding β,β-
dihaloenones,8 however the reactions did not seem general.
The use of carbon dioxide as the synthon would mean the
need to break strong C-O bonds later in the synthesis. So we
selected carbon disulphide, as it is known to react well with
1,3-diketones,9 and because once alkylated, the carbon-
sulphur bonds of the ketene ditioacetals can be displaced by a
range of nucleophiles.10 So, diones 9 were treated with CS2
under basic conditions, trapping the dithioate intermediate
with methyl iodide to give ketene dithioacetals 10 (Scheme
1). The reactions proceeded in generally good yields (70-
80%), only the glycine-derived 10d was formed in a poor
16% yield (Table 2, entry 4), presumably because of the
increased ring-strain of forming an exocyclic double bond on
a 5-membered ring.
Scheme 1. General synthetic route of NAPs 2. (a) DCC (1.05
equiv), DMAP (1.2 equiv), DCM, 5 ºC, 48h, 92-99%. (b)
EtOAc, reflux, 2h, 0-88%. (c) CS2 (2.1 equiv), K2CO3 (2.1
equiv), DMF, rt, 2h, then MeI (2.1 equiv), rt, 2h, 16-83%. (d)
Ketone R2COMe
4
(2 equiv.), tBuOK (3 equiv.),
Table 1
Synthesis of Boc-protected diones 9
Entry
Amino Acid 7
Tricarbonyl 8
Yield%
94
Dione 9
Yield%
83
1
7a
7b
8a
8b
9a
9b
2
92
88
3
4
99
92
49
62
7c
8c
9c
7d
8d
9d

3
96
0
5
7e
8e
9e
Scheme 2. Synthesis of 4-thio-7,8-dihydro-1,6-naphthyridin-
5(6H)-ones. (a) Ketone R2COMe 4 (2 equiv.), tBuOK (3
equiv.), DMSO/THF, 25 ºC, 2h (b) NH4OAc (10 equiv),
AcOH, 80 ºC, 2h.
Table 2
Synthesis of ketene dithioacetals 10
Starting
Dione
Entry
1
ketene dithioacetals 10
Yield%
70
We were not presented with a straightforward solution to de-
symmetrise the ketene dithioacetals 10, so despite the low
yields of the condensation procedure, we synthesised a series
of dihydronaphthyridinones 11 and oxidized them to their
corresponding sulphones 12 (Table 3).
9a
10a
2
83
9b
10b
3
4
72
16
9c
10c
10d
Table 3
Synthesis of methylthio-NAPs 11 and methylsulphonyl-NAPs
12 from ketene dithioacetal 10a
Entry
1
R2
Yield% of 11a Yield% of 12a
9d
42
55
99
11a
11b
12a
12b
We next turned to the condensation sequence to give the
central dihydronaphthyridinone core. Based on literature
precedent,10c,11 we developed a one-pot reaction, adding a
ketone 4 to the ketene dithioacetal 10 in the presence of
potassium tert-butoxide and cyclising the diketone
intermediate 14 in the presence of a large excess of
ammonium acetate under acidic conditions (Scheme 2).
2
100
3
4
5
31
8
85
67
11c
11d
11e
12c
12d
12e
Variation of bases, equivalents, orders of addition, reaction
temperatures and times failed to achieve any improvement of
the cyclisation yield which was at best around 50%. The
answer lay in the almost identical reactivity of the
methanethiol groups.12 To be able to condense with ammonia
and form the dihydronaphthyridinone core of 11, the
incoming enolate must displace the methanethiol group cis to
the piperidinedione ketone carbonyl (10→14). Displacement
of the trans methanethiol group would give intermediate 15,
incapable of subsequent cyclisation onto the amide carbonyl
of the piperidinedione ring and instead forming enamine 16
(Scheme 2).
11
77b
6
7
25
6c
81
11f
12f
11g
a R1 = H. b pyridine N-oxide obtained. c Product without the
Boc protecting group obtained.
Reactions with simple aliphatic ketones were not attempted to
avoid the additional complication of mixtures due to the two
possible enolates. We included cyclopropyl methyl ketone
(Table 3, entry 7) since it would only form a single enolate,
but the yield of the methylthio-NAP 11g was especially poor
in this case, and was accompanied by the premature cleavage
of the Boc group.
Of the other ketene dithioacetals, methyl substitution in the
dithioacetals 10b and 10c did not greatly affect the yield of
the cyclisation (data not shown). However, 5-membered
pyrrolidinedione 10d failed to cyclise, the increased ring-
strain of condensing a 6,5-bicyclic system the likely cause for
the failure.

4
Tetrahedron
The thioethers 11 were oxidised to the corresponding sulfones
12 with mCPBA (Scheme 1 and Table 3). Most of the
reactions proceeded smoothly. In the case of sulphone 12d,
the lower yield was due to the beginnings of over-oxidation of
the NAP core to its N-oxide (Table 3, entry 4). In the case
pyridine-containing thioether 11e (Table 3, entry 5), we
deliberately over-oxidised, obtaining the R2 pyridine N-oxide
12e in 77% yield.
3
4
5
6
7
160 ºC, 23hb
160 ºC, 6hb
70 ºC, 56ha
160 ºC, 5h
51
55
27
19
40
2c
2d
2e
2f
The final step of the synthesis was the introduction of the R3
amine 5. When we treated sulphone 12a with 3-
methoxyaniline in ethanol at reflux we observed a high
conversion to the Boc-protected product 17, which after
treatment with TFA gave the desired NAP 2a in 70% overall
yield over the two steps (Scheme 3 and Table 4, entry 1).
70 ºC, 18h;
160 ºC,0.5h
2g
8
160 ºC, 5h
75
2h
9
160 ºC, 5h
160 ºC, 5h
46
24
2i
2j
10
11
12
13
160 ºC, 10h
160 ºC, 10h
160 ºC, 5h
22
11
53
2k
2l
Scheme 3. Synthesis of NAPs 2. (a) Amine R3NH2 5, EtOH,
reflux, 18-48 h (b) TFA, CHCl3, rt, 1h, 27-70% over two
steps. (c) EtOH, 150-170 ºC (microwave), 0.5-2 h, 23-40%
over 2 steps . (d) Amine R3NH2 5, EtOH/THF, 150-170 ºC
(microwave), 0.5-23 h, 11-76%.
2m
70 ºC, 48h
160 ºC,0.5h
14
15
23
2n
2o
Encouraged, we set about displacing the sulfones 12 with a
range of aromatic and aliphatic amines 5 (Table 4). It soon
became apparent that some amines, especially electron poor
anilines or heteroaromatic amines reacted very slowly or
simply gave no reaction at all. In order to force the conditions,
we used microwave irradiation in sealed vessels to achieve
much higher temperatures. Poorly reactive amines did give
some conversion, but with overall low yields after extensive
reaction times. One beneficial consequence of microwave
irradiation at elevated temperatures was the thermal removal
of the Boc-protecting group from the NAP core, giving final
products 2 directly (Scheme 3).
70 ºC, 24ha
62c
a step 2: TFA, CHCl3, r.t., 1h. b THF as co-solvent. c Product
R3=4-piperidinyl.
To address the poor yields with some of the heteroaromatic
amines we developed an alternative synthetic route.
Treatment of sulphones 12 with 7N ammonia solution in
methanol under microwave conditions gave the amino NAPs
13 (Scheme 4). Initially, this reaction gave excellent yields of
the desired product, but the yields were very variable and
were especially poor (even zero) in larger scales. In these
cases, we observed a host of by-products arising from ring-
opening of the NAP lactam by either ammonia or methanol, in
addition to displacement of the sulphone group by either
methoxide or ammonia and various combinations thereof
(Scheme 4, 18). We solved this problem by first removing the
Boc group of 12 with TFA. Thus, the lactam behaved as a
resistant amide bond, rather than the weaker imide bond of
12. Ammoniolysis now smoothly gave the amino NAPs 13 in
high yields (Table 5).
Table 4
Synthesis of NAPs 2 by amine displacements
Yield
%
Entry
R2
R3-NH2 5
Conditions
1
70 ºC, 18ha
70
2a
2b
2
160 ºC, 9hb
76

5
R3Br 19
1
2
Pd
Pd
28
39
2k
2p
3
Pd
34
2q
4
5
6
Pd
42
14
46
2r
CuI
CuI
20a
20b
Scheme 4. Alternative synthesis of NAPs 2. (a) 7N NH3 in
MeOH, 100 ºC (microwave), 5 h, 0-99%. (b) TFA, CHCl3, rt;
then 7N NH3 in MeOH, 100 ºC (microwave), 5 h, 87-97%. (c)
Aryl bromide R3Br 19, Pd2(dba)3 (0.1 equiv), Cs2CO3 (1.4
equiv), Xanthphos (0.2 equiv), dioxane, reflux, 24 h, 14-46%
(d) Aryl bromide R3Br 19, CuI (0.1 equiv), (Me2NCH2)2 (0.2
equiv), K2CO3 (2 equiv), dioxane, 120 ºC, 24 h, 14-46%.
7
CuI
28
20c
a Pd = Pd2(dba)3
Table 5
Ammoniolysis of sulphones 12 to amino NAPs 13
Route (a)a
yield%
Route (b)a
yield%
To validate the molecular design of the NAPs, compound 2a
was tested against the PDE4 enzyme an showed an IC50 of 1.6
nM.
Entry
1
R2
Product
0-99
97
87
13a
Conclusion
In summary, we have developed a convergent 6 or 7 step
route to synthesise 3-point diverse NAPs 2 as potent PDE4
inhibitors. Yields of the key enolate addition/ammonia
condensation sequence were limited to a maximum of around
50%, but allowed rapid entry to the tetra-substituted core ring
system. The R3 group could be introduced either from
nucleophilic amines 5, or via a palladium-catalysed arylation
reaction with bromides 19. Biological results of these
compounds will be reported elsewhere.
2
48-92
13b
3
67
n.d.
13f
a See legend, Scheme 4. n.d. not done.
Finally, we could introduce the R3 group using aryl bromides
19 via a palladium-catalysed arylation reaction (Table 6). The
yields were modest, although un-optimised. More
importantly, we could access compounds which were
unavailable to us by the previous sulphone displacement
reaction. As a last twist, we found that the copper-catalysed
reaction gave arylation not of the primary amino group as we
required, but of the NAP amide nitrogen, giving regioisomers
28 (Table 6, entries 5-7).
Supporting data
Supplementary data (general experimental procedures and
spectral data) are available
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