Synthesis of sterically hindered 3,5,5-trimethyl 2,6-dioxo tetrahydro pyrimidine as HCV protease inhibitors

Article abstract of DOI:10.1016/j.tetlet.2009.12.129

An efficient route for the synthesis of sterically hindered substituted and unsubstituted 2,6-dioxo tetrahydropyrimidines from amine 1 is described. These analogs are active against HCV NS3 serine protease. The biological data for some of the representati

Full text of DOI:10.1016/j.tetlet.2009.12.129

Tetrahedron Letters 51 (2010) 1276–1279
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Tetrahedron Letters
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Synthesis of sterically hindered 3,5,5-trimethyl 2,6-dioxo tetrahydro
pyrimidine as HCV protease inhibitors
*
Latha G. Nair , Stephane Bogen, Ronald J. Doll, N.-Y. Shih, F. George Njoroge
Merck Research Laboratories, 2015 Galopping Hill Road, Kenilworth, NJ, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient route for the synthesis of sterically hindered substituted and unsubstituted 2,6-dioxo tetra-
hydropyrimidines from amine 1 is described. These analogs are active against HCV NS3 serine protease.
The biological data for some of the representative examples are also reported.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 3 November 2009
Revised 21 December 2009
Accepted 22 December 2009
Available online 28 December 2009
Although the hydantoins and their analogs are well docu-
mented in the literature,1–6 the corresponding six-membered
heterocyclic analogs viz., tetrahydropyrimidines, are still to be ex-
plored. It has been recognized that tetrahydropyrimidines are
important intermediates in the catabolism of pyrimidines and their
derivatives are assumed to play an important role in the nucleic
acid synthesis.7 A survey of literature revealed that relatively little
attention has been focused on tetrahydropyrimidine, except a few
early reports and patents. The known methods for the synthesis of
traces of (<5%) five-membered cyclized urea 12a. Compound 6 was
converted to the N-methyl derivative 7 with Cs2CO3 and MeI in
DMF (Scheme 2).18
Attempts to convert 1 to 6 via a one-pot cyclization of urea 5
with triethyl amine in THF were unsuccessful even at elevated
temperatures (80–150 °C) and with a longer reaction time.
Previous structure–activity relationship studies (SAR) in the
HCV protease inhibitor program have shown that when the hydan-
toins16 and lactams19 were substituted with gem-dimethyls, the
dihydropyrimidines include the condensation of
a,b-unsaturated
acids with urea to afford the dihydrouracil in low yield,8 the deth-
iation of 5,5-dialkyl-substituted 6-thio 5,6 dihydrouracils using
Raney Nickel,9 and another protocol with unreported yields.10 Syn-
thesis and the biological importance of substituted uracils and thio
uracils are also known.11–13 Reduction of barbiturates to the corre-
sponding dihydro dioxo pyrimidine14 and synthesis of dihydropy-
rimidine 2,4-dione from acrylic acid and urea are reported in
1960s.15
MsCl, Pyr
NaN3,DMF
BocHN
BocHN
OMs
OH
80 oC, 2hrs,75 %
CH2Cl2, 92 %
2
3
Pd/C, H2 (1 atm.)
EtOAC, 100 %
BocHN
BocHN
NH2
N3
In our SAR studies on the P3 cap area of the HCV NS3 protease
inhibitor,16 we were interested in hydantoins and their six-mem-
bered analogs. To our knowledge there is no report on the synthe-
sis of N-linked dihydro dioxo pyrimidines (dihydro uracils) from
amines or alcohols and herein we report the synthesis of the
unsubstituted and trimethyl-substituted dihydro dioxo pyrimi-
dines 6 and 15 from amine 1 and the biological activity of their
analogs.
Amine 1 was synthesized from the commercially available tert-
leucinol via mesylation, and azide displacement followed by reduc-
tion (Scheme 1).17
Amine 1 was treated with the ethyl isocyanato propionate and
triethyl amine in THF under reflux conditions to afford the urea 5.
The urea 5 was cyclized to the desired product 6 by treating with
NaH in THF at ambient temperature in excellent yields along with
1
4
Scheme 1.
O
OEt
OCN
O
O
BocHN
N
H
N
H
OEt
1
Et3N,THF
80o
C
5
O
O
MeI, Cs2CO3
NaH,THF
0-25 oC, 80 %
BocHN
BocHN
N
DMF,RT, 98%
N
N
NH
O
7
O
6
* Corresponding author. Tel.: +1 908 740 4692; fax: +1 908 740 7305.
E-mail addresses: latha.nair@spcorp.com, lathaanil@yahoo.com (L.G. Nair).
Scheme 2.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.129

L. G. Nair et al. / Tetrahedron Letters 51 (2010) 1276–1279
1277
O
O
PtO2,H2
NaHCO3,phosgene
OEt
OEt
N
H2N
Acetic acid
DCM
8
9
O
O
O
Et N, THF
1
,
3
BocHN
N
H
N
H
OEt
OEt
OCN
80 oC, 60%
10
11
CO2Et
R2
O
N
O
NH
NaH,THF
0-80 oC, 95 %
Figure 2. Minimum energy configuration of 11.
R1
HN
a, R1=R2=H
12
b, R1=R2=Me
O
O
1. 4M HCl/ dioxane,1hr
(Bn)2N
N
H
N
H
OEt
11
2. BnBr, K2CO3, EtOH
100 oC, 2hr, 84 %
Scheme 3.
13
O
O
inhibitor had a profound effect on in vitro and in vivo profiles.
Hence our next approach was to synthesize the dimethyl and tri-
methyl tetrahydro pyrimidine dione analogs for our SAR study.
Synthesis of the trimethyl derivative started with the nitrile 8.
Conversion of nitrile to the isocyanate 10 was achieved via reduc-
tion followed by treatment of the resulting amine 9 with phosgene
(Scheme 3). Urea 11 was synthesized via the reaction of isocyanate
10 with the amine 1 under basic conditions. Attempts to synthe-
size the 5,5-dimethyl-substituted tetrahydrodioxo pyrimidine via
the cyclization of the urea 11 resulted in exclusive formation of
the five-membered cyclic urea derivative 12b (Scheme 3). This
may be attributed to the geometry of the intermediate in which
the gem-dimethyl groups block the attack of the amide nitrogen
to the ester carbonyl (Fig 2). According to the minimum energy cal-
culations, steric energy for 11 (Fig 2) is 30.22 kcal/mol whereas
that for 5 (Fig 1) is only 20.02 kcal/mol.
MeI,Cs2CO3
DMF,RT, 90 %
NaH,THF
(Bn)2N
(Bn)2N
N
N
N
100oC, 90%
NH
O
O
14
15
Scheme 4.
O
O
1. 4M HCl/ dioxane,1hr
2. BnBr, K CO , EtOH
(Bn)2N
5
N
H
N
H
OEt
2
3
100 oC, 2hr, 84%
17
O
1.NaH, THF, 100 oC, 2hr
(Bn)2N
2. NaH, MeI, THF
100 oC, 2hr, 61%
N
The urea 11 was then N-deprotected and re-protected with ben-
zyl groups to avoid the side product resulting from the reaction
with the tert-butoxy carbonyl group. Urea 13 was treated with
NaH at 100 °C to afford the desired product 14 in 90% yield
(Scheme 4). The trimethyl derivative 15 was generated via the
methylation procedure described earlier.18
N
O
15
Scheme 5.
Alternatively, 15 can be constructed from urea 5. One-pot, two-
step addition of sodium hydride followed by sodium hydride and
methyl iodide to urea 17 afforded 15 in 61% yield in two steps
(Scheme 5).
Surprisingly, deprotection of the N-benzyl group under hydro-
genation conditions (Pd/C, H2 or Pd(OH), H2) resulted in the forma-
tion of dihydroimidazole 18 as the sole product. However, reaction
of the hydrochloride salt of 15 with Pearlman’s catalyst under
acidic conditions afforded the desired amine 19 ready for further
transformations. The amine hydrochloride 19 was transformed
to the isocyanate under standard conditions with phosgene
(Scheme 6).
N
N
O
O
Pd(OH)2/C, H2(1atm.)
3hrs, quantitative
(Bn)2N
N
N
N
O
15
18
1. HCl, ether
2. Pd(OH)2/C, H2(1atm.)
in 4M HCl/ dioxane
100%
O
N
O
Phosgene/DCM
OCN
H2N
HCl
NaHCO3
N
N
N
O
O
20
19
Scheme 6.
Compounds bearing these moieties were active against the HCN
NS3 Serine protease. Biological activities of representative exam-
ples are given in Table 1.
Figure 1. Minimum energy configuration of 5.

1278
L. G. Nair et al. / Tetrahedron Letters 51 (2010) 1276–1279
1. 4M HCl/dioxane, RT
2. P4NCO, DIPEA, CH2Cl2
tert-leucine
OMe
OMe
EDCI,HOOBt
DMF/CH2Cl2
N
H
N
O
N
HCl
O
O
N
O
O
22
21
1. LiOH, THF/MeOH/H2O
H
OH
OMe
N
N
N
O
N
2.
O
O
N
N
O
O
N
N
O
P
OH
NH2.HCl
P4
O
4
24
O
EDCI, HOOBt, DMF/CH2Cl2
23
25
O
Dess-Martin Periodinane.
N
N
O
N
O
N
N
P
O
4
O
26
Scheme 7. Synthesis of the P3-capped tetrahydrodioxo pyrimidines.
ine and other interactions between the inhibitors and the en-
zyme.25 The concentration required for inhibition of 90% of virus
replication, EC90, was obtained as a measure of replicon cellular po-
tency.26 Inhibitors were tested for the activity against one of the
most structurally closely related serine protease, human neutro-
phil elastase (HNE) to determine the selectivity between HCV
and HNE.
In conclusion we have developed a convenient and efficient way
to synthesize sterically hindered substituted dioxo tetrahydro
pyrimidines from amines. In our efforts toward the backup of our
clinical candidate22 (Boceprevir) in the HCV therapeutic area, we
have identified a novel class of compounds with dioxo tetrahydro
pyrimidines at the P4 area. Most of these analogs showed four to
sixfold improvement in the in vitro potency.
Table 1
Dioxo tetrahydro pyrimidine analogs as HCV NS3 protease inhibitors
O
N
N
N
O
O
P4
N
N
O
O
27
KÃi (nM)
Compound
P4
IC90 (nM)
150
HNE/HCV
4300
O
HN
N
28
4
O
Acknowledgments
O
O
L.G.N. would like to thank Structural Chemistry and Virology
groups of Schering-Plough for spectral analysis and in vitro assays,
respectively.
N
N
N
N
29
30
7
60
1400
180
O
O
References and notes
92
NA
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Inhibitors 28, 29, and 30 were synthesized according to the gen-
eral Scheme 7. The gem-dimethyl proline derivative 21 was pre-
pared by a modified published procedure.20 21 was coupled to
the P3N-Boc tert-leucine21,22 followed by acidic deprotection of
the Boc and subsequent coupling with the P4 isocyanate to afford
the P4 methyl ester 23. Hydrolysis of the methyl ester 23 with
LiOH to the corresponding acid followed by coupling to the norleu-
cine allyl amide derivative 24 under EDCI, HOOBt conditions gave
the hydroxy allyl amide intermediate 25. This upon oxidation with
Dess–Martin Periodinane afforded the keto amide of type 26.
All inhibitors were tested in the HCV continuous enzymatic as-
say23 using the NS4A-tethered single chain NS3 serine protease.24
The KÃi values reflected the equilibrium constant determined by
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The mixture was diluted with ethyl acetate (100 mL), washed with water
(25 mL Â 3) and with brine (20 mL Â 2), and dried over anhyd sodium sulfate.
The solvent was filtered and evaporated off. The crude product was purified via
flash column (10–40% ethyl acetate–hexane) to isolate 7 (808 mg, 98%) as a
white solid.: 1H NMR (300 MHz, CDCl3-d6) d 4.62 (d, J = 10.98 Hz, 1H), 3.87–
3.83 (m, 1H), 3.62–3.60 (m, 1H), 3.59–3.57 (m, 1H), 3.28–2.26 (m, 2H), 3.00 (s,
3H), 2.66–2.64 (m, 2H), 1.38 (s, 9H), 0.98 (s, 9H); 13C NMR (75 MHz, CDCl3) d
168.99, 162.19, 156.11, 78.39, 57.69, 42.94, 41.12, 36.48, 35.91, 35.37, 33.79,
31.59, 31.42, 28.41, 26.38, 26.18.
19. Nair, L.; Sannigrahi, M.; Pinto, P.; Bogen, S. L.; Prongay, A.; Saksena, A.;
Girijavallabhan, V.; Cheng, K.-C.; Tong, X.; Shih, N.-Y.; Njoroge, F. G. Bioorg.
Med. Chem. Lett. 2010, 20, 567.
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T.-M.; Girijavallabhan, V. J. Org. Chem. 2002, 67, 2730; (b) Arasappan, A.; Chen,
K. X.; Njoroge, F. G.; Parekh, T. N.; Girijavallabhan, V. J. Org. Chem. 2002, 67,
3923.
16. Chen, K. X.; Nair, L.; Vibulbhan, B.; Yang, W.; Arasappan, A.; Bogen, S. L.;
Venkatraman, S.; Bennett, F.; Pan, W.; Blackman, M. L.; Padilla, A. I.; Prongay, A.;
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18. Experimentals and NMR for 6 and 7: To the amine (1 g, 4.6 mmol) dissolved in
THF (20 mL) were added the ethyl isocyanato acetate (987 mg, 6.9 mmol) and
triethyl amine(2.78 g, 27.6 mmol) at room temperature and then heated at
80 °C for overnight. The solvent and the volatiles were evaporated off and the
crude product (urea 5) was used for next step without purification. The urea 5
was dissolved in THF (10 mL) and NaH was added (3.68 g, 9.2 mmol, 60% in
mineral oil) at room temperature under nitrogen atmosphere and stirred for
5 h at the same temperature. The reaction mixture was quenched with cold
water, extracted with ethyl acetate, washed with brine, and dried over anhyd
sodium sulfate. The solvent was filtered and evaporated off. The crude product
was purified via flash column (10–40% ethyl acetate–hexane) to isolate 6 (1.16
g, 3.7 mmol) as an amorphous white solid.: 1H NMR (300 MHz, CDCl3-d6) d 5.86
(br s, 1H), 4.56 (d, J = 10.98 Hz, 1H), 3.89–3.84 (m, 2H), 3.73–3.63 (m, 1H),
3.36–3.32 (m, 2H), 2.72–2.64 (m, 2H), 1.38 (s, 9H), 0.95 (s, 9H).;13C NMR
(75 MHz, CDCl3) d 169.48, 156.21, 154.91, 78.59, 57.62, 40.33, 35.43, 33.89,
22. For Boceprevir: Venkatraman, S.; Bogen, S.; Arasappan, A.; Bennet, F.; Chen, K.;
Jao, E.; Liu, Y.-T.; Lovey, R.; Hendreta, S.; Huang, Y.; Pan, W.; Parekh, T.; Pinto,
P.; Popov, V.; Pike, R.; Ruan, S.; Santhanam, B.; Vibulbhan, B.; Wu, W.; Yang, W.;
Kong, J.; Liang, X.; Wong, J.; Liu, R.; Butkiewicz, N.; Chase, R.; Hart, A.; Agrawal,
S.; Ingravallo, P.; Pichardo, J.; Kong, R.; Baroudy, B.; Malcolm, B.; Guo, Z.;
Prongay, A.; Madison, V.; Broske, L.; Cui, X.; Cheng, K.-C.; Hsieh, T. Y.; Brisson,
J.-M.; Prelusky, D.; Korfmacher, W.; White, R.; Bogdanowich-Knipp, S.;
Pavlovsky, A.; Bradley, P.; Saksena, A. K.; Ganguly, A.; Piwinski, J.;
Girijavallabhan, V.; Njoroge, F. G. J. Med. Chem. 2006, 49, 6074.
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Meister (Ed.), Adv. Enzymol., 1988, 61, 201.
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F.; Koch, J.-O.; Herian, U.; Theilmann, L.; Bartenschlager, R. Science 1999, 285,
110.
31.75, 28.44, 26.47. Compound
6 (790 mg, 2.52 mmol) was dissolved in
DMF(5 ml) and Cesium carbonate(1.23 g, 3.78 mmol) was added to it at room
temperature under nitrogen atmosphere. The mixture was cooled down to ice
temperature and MeI (0.784 mL, 12.6 mmol) was syringed out to this. It was
stirred for overnight allowing the temperature to rise to room temperature.