Novel approach for the synthesis of five-membered-ring-fused pyrazinones

Article abstract of DOI:10.1002/ejoc.201000435

We describe a new route to access important pharmaceutical intermediates for the synthesis of constrained fused pyrazolones. These compounds are prepared in five to seven steps with a good overall yield from glycine methyl ester and commercial propanediol

Full text of DOI:10.1002/ejoc.201000435

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000435
Novel Approach for the Synthesis of Five-Membered-Ring-Fused Pyrazinones
Vincent Gembus,*[a] Solenn Janvier,[b] Jean-Pierre Lecouvé,[b] Philippe Gloanec,[c]
Francis Marsais,[a] and Vincent Levacher*[a]
Keywords: Alkylation / Heterocycles / Peptidomimetics / Pyrazinones / Serine protease inhibitor
We describe a new route to access important pharmaceutical
intermediates for the synthesis of constrained fused pyraz-
inones. These compounds are prepared in five to seven steps
with a good overall yield from glycine methyl ester and com-
mercial propanediol derivatives involving an intramolecular
alkylation of a glycine moiety as key step.
Introduction
Serine proteases are an important class of enzymes.[1] In-
deed, in mammals, these peptidases perform many impor-
tant functions, particularly in digestion, blood clotting, im-
mune system and inflammation. They are consequently in-
volved in the processes of diverse diseases (thrombosis, car-
diovascular disease, HCV infection etc.). That is the reason
why it is important to modulate the activity of these en-
zymes. During the last 30 years, peptidomimetic molecules
are taking an important part in medicinal chemistry.[2] In
this field of research, compounds containing a pyrazinone
moiety were widely studied due to their potential biological
activity, in particular as serine protease inhibitor.[3] More
precisely, the pharmaceutical industry has focused the at-
tention on the use of conformationally constrained peptide
analogues as serine protease inhibitors.[4] Then, diversely
substituted amino-fused pyrazinones were described as
thrombin,[4e] prolyl oligopeptidase[4f] or HCV NS3 protease
inhibitors.[4g] In all cases, the key intermediates for the prep-
aration of these fused compounds are pyrazinones 1a–c
(Scheme 1).
Scheme 1. Structures of key intermediates.
have focused our attention on a new route for the prepara-
tion of these pyrazinones 1 involving a Strecker reaction
and an intramolecular alkylation as key steps. In this paper,
we report a novel approach for a rapid and efficient synthe-
sis of these intermediates.
Results and Discussion
Our retrosynthetic strategy employs as key step an intra-
molecular alkylation of the glycine moiety of the pyr-
Until now, these fused intermediates were prepared in azinone 2 (Scheme 2). This product is prepared from the
seven steps from pyroglutamic acid in an overall yield of amino nitrile 3 through a classical cyclocondensation step
22%.[4e] However, reduction and cyanation steps proceeded with oxalyl chloride.[5] The amino nitrile 3 would be ob-
at very low temperature, and some reactions are difficult to tained by a modified Strecker reaction between the readily
be reproduced on a larger scale, thus limiting seriously the available glycine methyl ester and the aldehyde 4 derived
further development of this route. For these reasons, we from propanediol.
Our synthesis began with a modified Strecker reaction of
glycine methyl ester and the propanediol derivative 4 ob-
associé au CNRS (UMR COBRA-6014), INSA Université de tained by a Swern oxidation of the commercial monopro-
[a] Institut de Recherche en Chimie Organique Fine (IRCOF)
Rouen,
tected propanediol (Scheme 3). The amino nitrile 3 was iso-
Rue Tesnières, 76130 Mont-Saint-Aignan, France
lated in good yield by the addition of TMSCN in the pres-
ence of ZnCl2 in MeOH at –15 °C.[6] Then, the intermediate
pyrazinone 5 was synthesized by treatment of 3 with oxalyl
chloride in DCM in the presence of a catalytic amount of
DMF.[7] Selective debenzylation of 5 by treatment with
AlCl3 in DCM gave the alcohol 6 in 90% yield. This com-
pound was treated with thionyl chloride or mesyl chloride
Fax: +33-2-35522964
E-mail: vincent.gembus@insa-rouen.fr
[b] Oril Industries,
13 rue Auguste Desgenétais, 76210 Bolbec, France
[c] Institut de Recherches Servier,
11 rue des Moulineaux, 92150 Suresnes, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000435 or from
the author.
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V. Gembus, V. Levacher et al.
SHORT COMMUNICATION
Scheme 2. Retrosynthetic analysis.
Scheme 3. Reagents and conditions: (i) Swern conditions, 85%; (ii) GlyOMe·HCl, NEt3, ZnCl2, room temp., then TMSCN, –15 °C to
room temp., 85%; (iii) oxalyl chloride, DCM, room temp., then cat. DMF, 60%; (iv) AlCl3, DCM, room temp., 90%; (v) SOCl2, DCM,
cat. DMF, reflux, 80%; (vi) mesyl chloride, NEt3, DCM, 82%.
to give the chlorinated product 2b or the mesylate 2a in LDA or KHMDS in toluene at low temperature (Entries 2,
80% or 82% yield, respectively. With these products in 13). In the presence of DBU or under phase-transfer condi-
hand, the intramolecular alkylation of the mesylate 2a to tions, only the elimination product 7 was obtained (En-
the desired fused compound 1a was investigated next. A tries 6, 11). The use of potassium tert-butoxide (Entries 7,
variety of basic conditions were examined to realize this 8) or lithium tert-butoxide (Entries 9, 10) gave poor results,
transformation (Table 1).
most likely due to the formation of by-products arising
from transesterification and substitution of the chlorine
atom at the C-3 position. We finally found that the reaction
proceeds most efficiently when KHMDS was added to a
solution of compound 2a in THF at –15 °C (Entry 12). Un-
der these conditions, the substrate was totally consumed,
and the desired product 1a was isolated in a moderate yield
of 60%. However, this reaction could be significantly im-
proved up to 70% yield by using the chlorinated product
2b (Entry 13).
The introduction of a methoxy group at the C-3 position
was carried out in the presence of sodium methoxide in
MeOH (Scheme 4). Then, the O-demethylation was
achieved by heating 8 under strong acidic conditions (HBr
in acetic acid) providing the desired product 1b in a quanti-
tative yield. Finally, the dechlorination was performed by
hydrogenation in the presence of Pd/C and triethylamine to
furnish 1c.
Table 1. Intramolecular alkylation of pyrazinones 2a,b.
Entry
X
Reagent (equiv.)
Solvent, T [°C]
Yield of 1a/7[a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
Ms
LDA (1)
LDA (2)
NaH (1)
NaH (1)
LiTMP (1)
DBU (1)
tBuOK (4)
tBuOK (4)
tBuOLi (4)
tBuOLi (1)
THF, –78
toluene, –78 to r.t.
THF, reflux
DMF, r.t.
THF, –78
acetonitrile, 0
THF, 0
28:27
0:0[b]
40:40
[c]
22:18
0:100
15:0
51:10
19:0
toluene, 0
THF, 0
toluene, 0
toluene, 0
29:6
Ms NaOH (2)/TBAB (0.1)
0:100
31:30
0:0[b]
60:0
Ms
Ms
Ms
Cl
LiHMDS (2)
KHMDS (2)
KHMDS (2)
KHMDS (2)
toluene, –78 to r.t.
toluene, –78 to r.t.
THF, –15
THF, –15
70:0
[a] Isolated yield. [b] No reaction. [c] Degradation of starting mate-
rial.
Alternatively, the cyclization step could also be ac-
complished on pyrazinones 11 and 13, these last two being
obtained from dichloropyrazinone 5. After treatment of
dichloropyrazinone 5 with sodium methoxide, selective nu-
cleophilic substitution occurred at C-3 to give rise to pyrazi-
none 9 in 85% yield. Selective debenzylation was achieved
When lithium amide bases (LDA, LiTMP, LiHMDS)
were used, no selectivity was observed, and an equimolar
mixture of 1a/7 was obtained in moderate yields (Entries 1,
5, 12). A similar result was noted in the presence of sodium
hydride in THF (Entry 3). No reaction was observed with
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Eur. J. Org. Chem. 2010, 3583–3586

Five-Membered-Ring-Fused Pyrazinones
Scheme 4. Reagents and conditions: (i) MeONa, MeOH, room temp., 91%; (ii) 33% HBr in acetic acid, 40 °C, quant.; (iii) H2, Pd/C,
NEt3, EtOAc, quant.
Scheme 5. Reagents and conditions: (i) MeONa, MeOH, room temp., 85%; (ii) H2, Pd/C, MeOH, 85%; (iii) SOCl2, DCM, cat. DMF,
reflux, 82% from 10, 54% from 12; (iv) KHMDS, THF, –15 °C, 70% for both; (v) 33% HBr in acetic acid, 40 °C, quant. for both; (vi)
H2, Pd/C, EtOAc, then NEt3, 91%.
1
3
793 cm–1. H NMR (CDCl3, 25 °C, 300 MHz): δ = 5.17 (dd, JH-H
= 9.6, 3JH-H = 3.0 Hz, 1 H, CHCH2), 3.82 (s, 3 H, CH3), 3.22–3.15
(m, 2 H, CH2CH2CH), 2.66–2.38 (m, 2 H, CH2CH) ppm. 13C
NMR (CDCl3, 75MHz): δ = 168.9 (C), 151.4 (C), 144.3 (C), 140.5
(C), 119.8 (C), 63.7 (CH), 53.8 (CH3), 29.6 (CH2), 26.6 (CH2) ppm.
MS (EI): m/z (%) = 264 (20) [M + H]+·, 262 (32), 204 (90), 202
(100), 175 (62). C9H8Cl2N2O3 (263.08): calcd. C 41.09, H 3.07, N
10.65; found C 40.91, H 3.01, N 10.59.
by conducting the hydrogenation step in the presence of Pd/
C in methanol to afford pyrazinone 10 in 85% yield. In
contrast, both dechlorination and debenzylation occurred
smoothly when pyrazinone 9 was subjected to hydrogena-
tion in EtOAc in the presence of triethylamine to furnish
compound 12 in 91% yield. After chlorination of alcohols
9 and 12, the resulting pyrazinones 11 and 13 (isolated in
82% and 54% yield, respectively) were subjected to cycliza-
tion under the conditions previously optimized. In both
cases, the desired fused pyrazinones 1b and 1c were ob-
tained in 70% yield (Scheme 5).
Supporting Information (see footnote on the first page of this arti-
cle): Complete description of all of the experimental procedures as
well as the characterization of all new compounds.
Acknowledgments
Conclusions
This work was supported by Oril Industries and Institut National
des Sciences Appliquées (INSA) of Rouen.
We have accomplished an efficient and short synthesis of
these key intermediates by five-membered-ring fusion from
readily available starting materials. The application of this
route for the enantioselective synthesis of these compounds
is currently underway.
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Experimental Section
Typical Experimental Procedure for the Intramolecular Alkylation:
A solution of KHMDS (0.5  in toluene, 4 mL, 2 equiv.) was added
dropwise to a solution of 2b (0.30 g, 1 mmol) in THF (10 mL) at
–15 °C. The temperature was slowly (1.5 h) raised to 0 °C, and the
mixture was hydrolyzed at this temperature by addition of a satu-
rated aqueous solution of NH4Cl (10 mL), and the aqueous phase
was extracted with EtOAc (3ϫ). The combined organic phases
were washed with brine, dried (Na2SO4) and concentrated. Purifi-
cation by flash chromatography (EtOAc) gave pyrazinone 1a as a
pale yellow oil (0.185 g, 70%). Rf = 0.34 (EtOAc/cyclohexane, 3:1).
IR (KBr): ν = 2925, 1739, 1674, 1593, 1370, 1226, 1150, 1075,
˜
Eur. J. Org. Chem. 2010, 3583–3586
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V. Gembus, V. Levacher et al.
SHORT COMMUNICATION
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Published Online: May 19, 2010
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