Pyrimidine thioethers: A novel class of HIV-1 reverse transcriptase inhibitors with activity against BHAP-resistant HIV

Article abstract of DOI:10.1021/jm9800806

A series of pyrimidine thioethers was synthesized and evaluated for inhibitory properties against wild-type HIV-1 reverse transcriptase (RT) and an RT carrying the resistance-conferring mutation P236L. Modifications of both the pyrimidine and the function

Full text of DOI:10.1021/jm9800806

J . Med. Chem. 1998, 41, 3793-3803
3793
P yr im id in e Th ioeth er s: A Novel Cla ss of HIV-1 Rever se Tr a n scr ip ta se
In h ibitor s w ith Activity Aga in st BHAP -Resista n t HIV
Richard A. Nugent,* Stephen T. Schlachter, Michael J . Murphy, Gary J . Cleek, Toni J . Poel, Donn G. Wishka,
David R. Graber, Yoshihiko Yagi, Barbara J . Keiser, Robert A. Olmsted, Laurie A. Kopta, Steven M. Swaney,
Susan M. Poppe, J oel Morris, W. Gary Tarpley, and Richard C. Thomas
Departments of Medicinal Chemistry, Discovery Technology, and Infectious Diseases, Pharmacia & Upjohn,
Kalamazoo, Michigan 49001-0199
Received February 5, 1998
A series of pyrimidine thioethers was synthesized and evaluated for inhibitory properties against
wild-type HIV-1 reverse transcriptase (RT) and an RT carrying the resistance-conferring
mutation P236L. Modifications of both the pyrimidine and the functionality attached through
the thioether yielded several analogues, which demonstrated activity against both enzyme types,
with IC50 values as low as 190 nM against wild-type and 66 nM against P236L RT. Evaluation
of a select number of pyrimidine thioethers in cell culture showed that these compounds have
excellent activity against HIV-1IIIB-WT and retain good activity against a laboratory-derived
HIV-1MF delavirdine-resistant variant.
In tr od u ction
RT mutation increased the sensitivity of this mutant
enzyme to the inhibitory effects of 2, compared to wild-
type RT. This report focuses on preliminary investiga-
tions aimed at improving the activity of pyrimidine
thioethers versus P236L RT, through modification of the
pyrimidine ring substitution and variation of the sub-
stitution on the C-2 sulfide.
The reverse transcriptase (RT) of the human immu-
nodeficiency virus type 1 (HIV-1) is a proven target for
inhibition of HIV-1 replication.1-3 Several HIV-1 non-
nucleoside RT inhibitors (NNRTIs), including Pharma-
cia & Upjohn’s BHAP, delavirdine (DLV) (1),4,5 Boe-
hringer Ingelheim’s nevirapine,6 and Merck’s L-697,661,7
have demonstrated potent inhibition of HIV-1 replica-
tion in cell culture. Recently, both delavirdine (Rescrip-
tor tablets) and nevirapine (Viramune) have been
approved for therapeutic intervention in HIV-1-infected
individuals.
The dynamics of HIV-1 infection,8,9 in combination
with the high error rate arising from a lack of a
proofreading function during reverse transcription of the
HIV RNA genome, leads to the generation of a qua-
sispecies from which variants are selected by drug
treatment. Numerous RT mutations have been identi-
fied (singly or in combination) following selection of
resistant virus either in cell culture or in the clinic. For
example, nevirapine10 and L-697,66111 both select for
highly resistant virus which expresses a mutant RT
with a tyrosine-to-cysteine substitution at amino acid
181 (Y181C). This substitution in RT confers broad
cross-resistance to most NNRTIs currently in develop-
ment. In contrast, the BHAPs, such as DLV, preferen-
tially select in vitro for a proline to leucine modification
at amino acid 236 (P236L).12 Previous work had shown
that rather than imparting cross-resistance, the P236L
mutation generates an RT which retained sensitivity
or was actually sensitized to the inhibitory action of the
other NNRTIs.12,13 Selection of variants with distinct
resistance profiles (e.g., P236L) that retain sensitivity
to other NNRTIs would suggest that treatment with one
NNRTI could be effectively followed with others.
Earlier we reported that the pyrimidine thioether 2
was a good inhibitor of HIV-1 RT.14 This class of
compounds was identified from our efforts to discover
and develop NNRTIs effective against DLV-resistant RT
and virus. Further evaluation revealed that the P236L
Ch em istr y
Initially we investigated changes in the aryl group
on the right-hand side of the molecule. Following the
described procedure for the synthesis of 2,15 4-ami-
nothiouracil (3) was treated with NaOH in aqueous
EtOH at room temperature and then with 2-(bromo-
methyl)naphthalene to give 4 (R ) 2-naphthyl). This
was reacted with 1.5 equiv of POCl3 and 1 equiv of
2-picoline at reflux to give 5 (R ) 2-naphthyl) (Scheme
1, method A). We prepared many analogues in this
manner, without isolation of the intermediate amino-
hydroxypyrimidine, using the appropriate alkyl or ben-
zyl halides.
However, we sought an alternative route that would
avoid the use of POCl3 after the right-hand pieces were
attached and enable the synthesis of pyrimidines with
reactive or acid-sensitive side chains. Thus, 40 was
converted to 41 (Scheme 1) by alkylation with p-
methoxybenzyl chloride, treatment with POCl3/2-pi-
coline, and ammonolysis with NH4OH in CH3CN.16
Removal of the protecting group was accomplished by
treating 41 with an excess of CH3SO3H in CH2Cl2, and
the product was isolated by careful precipitation with
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3794 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20
Nugent et al.
Sch em e 1a
To investigate the importance of the thioether linker,
we prepared various analogues in which the sulfur was
replaced with oxygen, nitrogen, and carbon (Scheme 6).
4-Amino-2,6-dichloropyrimidine, 68, was treated with
appropriate alkoxides to prepare the ether derivatives
(69-72). 2-Amino-4,6-dichloropyrimidine, 73, was alky-
lated with (bromomethyl)naphthalene and then heated
with NH3/MeOH at 100 °C in a sealed tube to give the
substituted amine 74. To create an alkyl chain to the
aromatic group, 75 was treated with Ms-Cl, followed by
KCN to give the nitrile 76.17 76 was transformed to an
imido ether with HCl/EtOH and then to the amidine
77. Finally, this was converted to 78 via reaction with
ethyl cyanoacetate and then treatment with POCl3. The
thioethers 5 and 33 were also oxidized to sulfones 79
and 80 and to a sulfoxide, 81.
a
Reagents: (a) RCH2Br, NaOH, EtOH, H2O; (b) POCl3, 2-pi-
coline; (c) 4-methoxybenzyl bromide, NaOH, EtOH, H2O; (d)
NH4OH, CH3CN; (e) MsOH.
Resu lts a n d Discu ssion
Sch em e 2a
Replacement of the phenyl moiety of lead structure 2
by diverse alkyl and aryl groups led to the series of
compounds shown in Table 1. As indicated, the 2- and
1-naphthyl analogues, 5 and 6, exhibited good inhibition
against both enzymes (relative to 2). Saturation of the
phenyl ring of 2 led to the less potent cyclohexyl
analogue 7, which showed only modest activity against
the wild-type enzyme but no detectable activity versus
P236L. The nonyl derivative 8 showed no activity.
Introduction of an acid, ester, or amide residue on a
short alkyl chain, as in 9, 10, or 11, also gave inactive
compounds. Increasing the distance between the sulfur
and the phenyl of 2 by a single carbon (12) eliminated
activity, while deletion of the methylene linker of 2
yielded an inactive compound (data not shown). How-
ever, a rigid olefin residue, as in 13, improved the
inhibition versus the P236L enzyme to levels better than
those of 5. This suggests that the enzyme pocket can
accommodate a large, but flat, hydrophobic group at this
position. An analogue of 13, which is ring-constrained
(14), shows dramatically reduced activity against both
enzymes. Taken together, 14 and 15 can be seen as
analogues of 5 and 6 in which the A-ring is partially
saturated. Although 15 shows good activity versus
P236L RT, its activity against wild-type is greatly
reduced. Saturation of the B-ring and introduction of
added bulk in the form of four methyl groups, such as
in 16, gave an inactive compound. Replacing the B-ring
of 5 with a dioxolane to give the piperonyl derivatives
17 and 18 significantly improved activity against both
enzymes. The introduction of a single chlorine onto the
parent ring system, 18, gave a compound with IC50
values < 100 nM against both enzymes.
a
Reagents: (a) ArCH2Br, NaOH, EtOH, H2O; (b) POCl3,
2-picoline; (c) R1R2NH, CH2Cl2, Et3N.
Et2O to give 42. This was treated with the appropriate
alkylating agent in the presence of aqueous NaOH/
EtOH (method B).
To study the substitution of the pyrimidine ring, we
converted 40 to 43 and 44 by alkylation with benzyl
bromide or 2-(bromomethyl)naphthalene, respectively,
followed by POCl3/2-picoline (Scheme 2). These inter-
mediates were treated with amines to give the desired
pyrimidines 45-51. The acetamido analogue of 5 was
prepared through transacylation from EtOAc to give 52.
2 was converted to 54 with pyrrolidine at reflux for 60
h. 53 and 55-57 were prepared by standard methods.
Direct substitution of the chloro moiety by carbon was
not possible, so 60, 64, and 67 were assembled from the
appropriate â-keto esters. The 4-CF3 group was intro-
duced from the commercially available â-keto ester,
which was transformed to the uracil analogue 58
(Scheme 3). This was converted to the chloride 59 with
POCl3/2-picoline and then to the amine 60, by treatment
with NH3/MeOH. Other functionality, however, was not
obtained quite as easily.
The 4-cyanopyrimidine 64 was synthesized (Scheme
4) beginning with the â-keto ester by first conversion
to the acetal 61, which was then hydrolyzed and
converted to the oxime 62. This was never isolated but
rather treated immediately with POCl3/2-picoline re-
sulting in chlorination of the pyrimidine ring and
simultaneous dehydration of the oxime to the nitrile 63.
Finally, treatment with NH4OH/THF gave 64.
The 4-ethoxycarbonyl derivative 67 was synthesized
(Scheme 5) from thioorotic acid, 65, by alkylation with
2-(bromomethyl)naphthalene, conversion to the ethyl
ester, and then chlorination to give 66. Attempts to
directly convert 66 to 67, using NH4OH in various
organic solvents or anhydrous NH3/MeOH, were unsuc-
cessful, so 66 was first transformed to the azide and
then reduced with SnCl2 to give 67 in 62% yield for both
steps.
Having identified the naphthalene moiety as a suit-
able replacement for phenyl, we next explored the effects
of varying substitution on the pyrimidine ring. As can
be seen from Table 2, replacement of the amino group
of 2 or 5 with various groups (43-53) led to significantly
reduced levels of activity against both enzymes. Initial
analogues (4, 54, 55) in which the chlorine was replaced
were similarly inactive. Replacing either the primary
amino or chloro groups of 5 with a simple proton
provided 56 and 57, which demonstrated less activity
than 5 but essentially equivalent activity as 2. In
contrast, the 4-(trifluoromethyl)pyrimidine 60 was
slightly less potent than 5 demonstrating that the

Pyrimidine Thioethers
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20 3795
Sch em e 3a
a
Reagents: (a) thiourea; (b) 2-(bromomethyl)naphthalene, NaOH, EtOH, H2O; (c) POCl3, 2-picoline; (d) NH3/MeOH.
Sch em e 4a
a
Reagents: (a) thiourea; (b) 2-(bromomethyl)naphthalene, NaOH, EtOH, H2O; (c) 50% HOAc; (d) NH2OH‚HCl, NaOAc; (e) POCl3,
2-picoline; (f) NH4OH, THF.
Sch em e 5a
Sch em e 6a
a
Reagents: (a) 2-(bromomethyl)naphthalene, NaOH, EtOH,
H2O; (b) EtOH, CDI, DMF; (c) POCl3, 2-picoline; (d) NaN3, DMF;
(e) SnCl2, EtOH.
trifluoromethyl moiety is a conservative replacement for
chlorine. Other electron-withdrawing groups were not
as good. The 4-cyanopyrimidine 64 was less active than
60, while the 4-ethoxycarbonyl 67 was inactive. These
results suggest that the optimal RT activity depends on
a delicate balance between a small electron-withdrawing
group at C-4 and a primary amine at C-6 on the
pyrimidine.
Derivatives, which modify the thioether linkage by
replacing the sulfur with other heteroatoms or a meth-
ylene group, are presented in Table 3. Introduction of
an ether bridge led to analogues (69-72) with reduced
activity against wild-type RT relative to the correspond-
ing sulfur-containing derivative, although activity ver-
sus P236L is still observed. Derivatives with amino (74)
or methylene (78) in place of the sulfur are essentially
inactive. Oxidation of the sulfur diminished the activity
a
Reagents: (a) RCH2OH, 50% NaH; (b) 2-naphthyl-CH2Br,
NaOH, EtOH, H2O; (c) NH3/MeOH; (d) MsCl, Et3N; (e) KCN, DMF;
(f) HCl, EtOH; (g) EtO2CCH2CN, NaOMe, MeOH; (h) POCl3,
2-picoline.
of the molecules, as 79-81 showed slight suppression
of the P236L enzyme, but only at higher doses.

3796 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20
Nugent et al.
Ta ble 1. Inhibition of HIV-1 Reverse Transcriptase: Effects
of Thiol Substitution on HIV-1 Reverse Transcriptase
Inhibition
Ta ble 2. Effects of Pyrimidine Substitution on HIV-1 Reverse
Transcriptase Inhibition
% inhibition at 10 µMa,b
no.
R4
R6
Rc
wild-type
P236L
1
2
5
NA
Cl
Cl
NA
NA
Ph
Nap
Ph
Nap
Ph
Ph
(0.17)
(6.66)
87 (0.46)
19
0
14
17
26
ND
35
47
(3.57)
(1.47)
96 (0.15)
25
23
30
3
6
31
41
47
17
53
5
NH2
NH2
Cl
Cl
PrNH
43 Cl
44 Cl
45 Cl
46 Cl
47 Cl
48 Cl
49 Cl
50 Cl
51 Cl
52 Cl
53 Cl
HO(CH2)3NH
cyclohexylamino Ph
NH2-NH
pyrrolidino
piperidino
1-imidazolyl
AcNH
Ph
Ph
Ph
Nap
Nap
12
30
Ph
Nap ND
54 pyrrolidino NH2
Ph
3
0
4
OH
NH2
NH2
H
NH2
NH2
NH2
NH2
Nap
Ph
10
0
61
50
94 (0.29)
84
17
4
4
86
71
94 (0.43)
93
24
55 Me
56 Cl
57
60 CF3
64 CN
67 CO2Et
Nap
Nap
Nap
Nap
Nap
H
a
b
See legend to Table 1. ND, not determined; NA, not ap-
plicable. c Ph, phenyl; Nap, 2-naphthyl.
Ta ble 3. Effect of Altering the Heteroatom Linkage on HIV-1
Reverse Transcriptase Inhibition
a
Numbers in parentheses are IC50 values determined at eight
% inhibition at 10 µMa,b
drug concentrations.
no.
X
R
wild-type
P236L
Realizing that the activity could best be adjusted by
modification of the aryl piece of the molecule, the
dramatic activity of 13 led to the synthesis of additional
olefinic analogues. As shown in Table 4, replacing the
phenyl of 13 with methyl 19 gave good inhibition
against P236L and wild-type, although not as good as
13. This is the smallest molecule to show inhibition,
but the results suggested that increasing the steric bulk
might also increase the activity. The methyl ester 20
had activity comparable to that of the original lead 2.
Converting this to tertiary amides 21 and 22 gave more
potent compounds, but the secondary amide 23 was
significantly less active. This suggests the placement
of the amide within a highly lipophilic pocket of the
enzyme, which is disrupted in the secondary amide
either through the presence of the hydrogen-bonding
proton or through poor geometry.
The improvement in activity seen with 5 and 22,
which is likely due to an increase in lipophilicity, led to
a study of substituted phenyl derivatives of 2. System-
atic introduction of a methyl group to each position of
the phenyl ring of 2 was investigated as an initial
approach toward locating sites for improving activity.
As shown in Table 5, this strategy identified the
3-position as potency enhancing (24-26). Additional
derivatives at the 3-position, compounds 30-36, were
uniformly potent against P236L but could not be dif-
2
5
S
S
Ph
(6.66)
87 (0.46)
(1.47)
96 (0.15)
44
72
67
80
17
12
75
2-naphthyl
Ph
69
70
71
72
74
78
79
80
81
O
O
O
O
NH
CH2
SO
SO
SO2
1
25
2
63
9
ND
45
ND
ND
3-methylphenyl
1-naphthyl
2-naphthyl
2-naphthyl
2-naphthyl
2-naphthyl
3-bromophenyl
3-bromophenyl
40
14
a,b
See legend to Table 2.
ferentiated. 37 showed significant suppression of both
wild-type and P236L enzymes, but at a level that did
not match that seen with 25.
Seven compounds that demonstrated the most potent
in vitro inhibitory activities against WT and P236L RTIs
(IC50 range: 0.06-0.47 and 0.05-0.16 µM, respectively)
were next evaluated for antiviral activity in cell cul-
ture.18 As shown in Table 6, all seven compounds
displayed submicromolar IC90 values against WT HIV-1
(HIV-1IIIB). The tertiary amide compounds 21 and 22
showed potencies similar to that of DLV. Although the
in vitro enzyme assay results indicated that the P236L
substitution sensitized RT to each of the seven com-
pounds compared to WT-RT, only 21 and 22 had
submicromolar IC90 values against the laboratory-

Pyrimidine Thioethers
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20 3797
Ta ble 4. Olefinic Pyrimidine Derivatives
Con clu sion
The pyrimidine thioethers constitute a novel series
of NNRTIs that display potent RT inhibitory activity
in vitro. Beginning with 2, our efforts have led to the
identification of pyrimidine thioether derivatives with
IC50 values against WT RT comparable to that of DLV
and, importantly, with potent activity against DLV-
resistant RT. Further evaluation identified two com-
pounds, 21 and 22, with marked activity versus WT and
DLV-resistant HIV-1 replication in cell culture. We
have continued our studies on this novel class of
NNRTIs, focusing on enhancing potency, broadening the
spectrum of antiviral activity to encompass additional
strains of drug-resistant HIV-1, including those express-
ing the Y181C mutation, and improving pharmacoki-
netic performance. Positive results in all these param-
eters will be reported in a subsequent manuscript.
% inhibition at 10 µMa,b
no.
R
method
wild-type
P236L
1
2
(0.17)
(6.66)
(0.19)
5
(3.57)
(1.47)
(0.066)
47
13
19
20
21
22
23
Ph
Me
A
A
B
B
B
B
CO2Me
78 (5.25)
99 (0.20)
98 (0.05)
40
93 (0.93)
99 (0.07)
99 (0.03)
55
CONMe2
CONEt2
CONHEt
a,b
See legend to Table 2.
Ta ble 5. Effects of Aryl Substitution on HIV-1 Reverse
Transcriptase Inhibition
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. Mass spectra, infrared spectra,
and combustion analysis were obtained by the Physical and
Analytical Chemistry Unit of Pharmacia & Upjohn. 1H NMR
spectra were obtained at 300 MHz on a Bruker AM 300 or at
400 MHz on a Bruker ARX 400 spectrometer using tetra-
methylsilane as an internal standard unless stated otherwise.
Melting points were measured on a Thomas/Hoover apparatus
and are uncorrected. Thin-layer chromatography was con-
ducted on Analtech GF silica gel plates. Column chromatog-
raphy was conducted at medium pressure using silica gel (E.
Merck, 70-230 mesh).
% inhibition at 10 µMa,b
no.
R
method
wild-type
P236L
2
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
41
H
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
(6.66)
(1.47)
4-Me
3-Me
2-Me
4-Ph
4-tBu
4-CO2Me
3-CO2Me
3-CF3
3-MeO
3-I
3
5
96 (0.28)
98 (0.045)
6-Am in o-2-[(1-n a p h th a len ylm eth yl)th io]-4(1H)-p yr im i-
d in on e (4). Compound 3 (2.1 g, 15 mmol) was slurried in
EtOH (15 mL) at 50 °C, then treated with 3.25 N NaOH (4.75
mL, 15.5 mmol), and stirred for 30 min. 2-(Chloromethyl)-
naphthalene (3.43 g, 15.5 mmol) was added slowly over 5 min.
After the mixture stirred for 15 min, H2O (10 mL) was added
to the resulting slurry, and the reaction was allowed to stir
for 30 min. After cooling to room temperature, the solid was
collected, washed with 2 × H2O and 1 × EtOH, and then dried
overnight to give pure 4: 3.19 g (11.2 mmol, 75%); mp 247-
2
0
8
20
37
56
6
15
93 (0.33)
80
94 (0.23)
91
70 (0.98)
ND
97 (0.16)
89
3-Br
3-Cl
94 (0.76)
ND
97 (0.14)
65
1
3-F
ND
79
250 °C (DMF/H2O); H NMR (DMSO) δ 7.99 (s, 1 H), 7.85-
3,4-Cl2
3,5-Br2
3,5-Cl2
4-MeO
80 (0.49)
ND
ND
94 (0.062)
7.88 (m, 3 H), 7.48-7.58 (m, 3 H), 6.59 (s, 2 H), 4.93 (s, 1 H),
4.49 (s, 2 H); MS (EI) m/z 283 (M+). Anal. (C15H13N3OS) C,
H, N.
73
65
63
25
Gen er a l P r oced u r e for th e Syn th esis of 2-(Su bstitu ted
th io)ch lor oa m in op yr im id in e Der iva tives. Meth od A.
6-Ch lor o-2-[(2-n a p h t h a le n ylm e t h yl)t h io]-4-p yr im id i-
n a m in e (5). Compound 4 (2.47 g, 9.10 mmol) was added to
POCl3 (9 mL) and 2-picoline (1.40 mL, 13.6 mmol) and then
stirred at reflux overnight. The thick, gummy reaction
mixture was then poured onto ice and neutralized with NH4-
OH. This mixture was heated to boiling with stirring for 60
min, during which time a solid formed. If needed, additional
NH4OH was added to keep the pH > 7. The solid was filtered
and washed with H2O. The crude was chromatographed
(hexane/EtOAc, 3:1) and then recrystallized from heptane to
give 5 as a white solid: 1.03 g (3.46 mmol, 38%); mp 98-100
°C; 1H NMR δ 7.89 (s, 1 H), 7.78-7.80 (m, 3 H), 7.44-7.54 (m,
3 H), 6.14 (s, 1 H), 4.97 (s, 2 H), 4.51 (s, 2 H); IR 1647, 1635,
1565, 1534 cm-1; MS (EI) m/z 301 (M+). Anal. (C15H12ClN3S)
C, H, N.
a,b
See legend to Table 2.
Ta ble 6. HIV-1 Reverse Transcriptase and Antiviral Activities
of Selected Compounds
HIV-1
RT IC50 (µM)a
IC90 (µM)b
compd
WT
P236L
HIV-1-WT
HIV-1MF-DLVr
delavirdine
0.26
0.47
0.19
0.20
0.06
0.28
ND
18
0.03
0.22
0.15
0.09
0.02
0.11
0.27
0.35
53.58
2.76
5.05
0.74
0.11
1.76
3.21
4.52
5
0.15
0.07
0.07
0.05
0.05
0.16
0.14
13
21
22
25
32
34
ND
a
b
6-Ch lor o-2-[(1-n a p h t h a len ylm et h yl)t h io]-4-p yr im id i-
n a m in e (6): 17%; mp 114-116 °C (heptane); 1H NMR δ 8.11-
8.13 (d, J ) 8.0 Hz, 1 H), 7.84-7.87 (d, J ) 9.4 Hz, 1 H), 7.76-
7.79 (d, J ) 8.2 Hz, 1 H); IR 1653, 1566, 1532 cm-1; MS (EI)
m/z 301 (M+). Anal. (C15H12ClN3S) C, H, N.
ND, not determined. IC90, concentration of drug that inhib-
ited p24 production by 90% in infected MT4 cells. Cell culture
assays were performed as previously described.18
derived DLV-resistant variant of HIV-1MF-DLVr. Thus,
the in vitro IC50 for this set of compounds against the
P236L RT did not strictly correlate with their respective
antiviral activities measured in cell culture infection
experiments.
6-Ch lor o-2-[(2-cycloh e xylm e t h yl)t h io]-4-p yr im id i-
1
n a m in e (7): 15%; mp 142-143 °C (EtOAc); H NMR δ 6.13
(s, 1 H), 4.90 (s, 2 H), 3.00 (d, J ) 6.7 Hz, 2 H), 1.87 (m, 2 H),
1.65 (m, 4 H), 1.23 (m, 3 H), 1.00 (m, 2 H); IR 1646, 1564,
1532 cm-1; MS (EI) m/z 257 (M+). Anal. (C11H16ClN3S) C, H,
N.

3798 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20
Nugent et al.
6-Ch lor o-2-[(1-n on yl)th io]-4-p yr im id in a m in e (8): 12%;
mp 97 °C (heptane); 1H NMR δ 7.26 (s, 2 H), 6.15 (s, 1 H),
3.00 (m, 2 H), 1.6 (m, 2 H), 1.25 (m, 12 H), 0.85 (m, 3 H); IR
(s, 2 H), 4.36 (s, 2 H); IR 1658, 1585, 1566, 1537 cm-1; MS
(EI) m/z 319 (M+). Anal. (C12H9ClF3N3S) C, H, N.
6-Ch lor o-2-[[(3-m eth oxyp h en yl)m eth yl]th io]-4-p yr im -
1648, 1564, 1533 cm-1; MS (EI) m/z 287 (M+). Anal. (C13H22
-
1
id in a m in e (32): 26%; mp 99 °C (hexane/EtOAc); H NMR δ
ClN3S) C, H, N.
7.19-7.24 (m, 1 H), 6.99-7.00 (m, 2 H), 6.78-6.81 (m, 1 H),
6.16 (s, 1 H), 5.03 (s, 2 H), 4.33 (s, 2 H), 3.80 (s, 3 H); IR 1651,
6-C h lo r o -2-[[1-(2-p h e n y l)e t h y l]t h i o ]-4-p y r i m i d i -
n a m in e (12): 16%; mp 127-128 °C; 1H NMR δ 7.25-7.35 (m,
5 H), 6.16 (s, 1 H), 4.9 (s, 2 H), 3.29-3.31 (m, 2 H), 3.04 (m, 2
H); IR 1642, 1571, 1533 cm-1; MS (EI) m/z 265 (M+). Anal.
(C12H12ClN3S) C, H, N.
6-Ch lor o-2-[(3-p h e n yl-2-p r op e n yl)t h io]-4-p yr im id i-
n a m in e (13): 23%; mp 117-119 °C (heptane); 1H NMR δ 7.37
(m, 2 H), 7.32-7.22 (m, 4 H), 6.65 (d, J ) 15.7 Hz, 1 H), 6.31
(dt, J ) 14.8, 7.2 Hz, 1 H), 6.17 (s, 1 H), 4.97 (s, 2 H), 3.94 (d,
J ) 7.2 Hz, 2 H), 1.64 (d, J ) 6.6 Hz, 3 H); IR 1621, 1564,
1524 cm-1; MS (EI) m/z 277 (M+). Anal. (C13H12ClN3S) C, H,
N.
6-Ch lor o-2-[[(1,2,3,4-t et r a h yd r o-1,1,4,4-t et r a m et h yl-
n a p h th -6-yl)m eth yl]th io]-4-p yr im id in a m in e (16): 13%;
mp 133-135 °C (EtOAc); 1H NMR δ 7.34-7.35 (m, 1 H), 7.23-
7.25 (m, 1 H), 7.14-7.17 (m, 1 H), 6.16 (s, 1 H), 5.03 (s, 2 H),
4.3 (s, 2 H); IR 1645, 1567, cm-1; MS (EI) m/z 361 (M+). Anal.
(C19H24ClN3S) C, H, N.
1641, 1564, 1533 cm-1; MS (EI) m/z 281 (M+). Anal. (C12H12
-
ClN3OS) C, H, N.
6-Ch lor o-2-[[(3-iod op h en yl)m et h yl]t h io]-4-p yr im id i-
n a m in e (33): 31%; mp 108 °C (hexane/EtOAc); 1H NMR δ 7.80
(s, 1 H), 7.55-7.58 (d, J ) 8.0 Hz, 1 H), 7.37-7.39 (d, J ) 8.0
Hz, 1 H), 7.00-7.05 (t, J ) 7.8 Hz, 1 H), 6.16 (s, 1 H), 5.13 (s,
2 H), 4.25 (s, 2 H); IR 1628, 1564, 1531 cm-1; MS (EI) m/z 377
(M+). Anal. (C11H9ClIN3S) C, H, N.
6-Ch lor o-2-[[(3-br om op h en yl)m eth yl]th io]-4-p yr im id i-
n a m in e (34): 24%; mp 91-92 °C (hexane/EtOAc); 1H NMR δ
7.58-7.59 (m, 1 H), 7.33-7.39 (m, 2 H), 7.14-7.19 (m, 1 H),
6.21 (s, 1 H), 5.28 (s, 2 H), 4.29 (s, 2 H); IR 1658, 1585, 1569,
1537 cm-1; MS (EI) m/z 329 (M+). Anal. (C11H9BrClN3S) C,
H, N.
6-Ch lor o-2-[[(3-ch lor op h en yl)m eth yl]th io]-4-p yr im id i-
n a m in e (35): 27%; mp 103-104 °C; 1H NMR δ 7.57-7.58 (m,
1 H), 7.30-7.36 (m, 2 H), 7.11-7.17 (m, 1 H), 6.19 (s, 1 H),
5.24 (s, 2 H), 4.25 (s, 2 H); IR 1635, 1617, 1566, 1532 cm-1
;
6-Ch lor o-2-[[(6-ch lor o-1,3-ben zodioxol-5-yl)m eth yl]th io]-
MS (EI) m/z 285 (M+). Anal. (C11H9Cl2N3S) C, H, N.
1
4-p yr im id in a m in e (18): 21%; mp 157-158 °C (toluene); H
6-Ch lor o-2-[[(3-flu or op h en yl)m eth yl]th io]-4-p yr im id i-
n a m in e (36): 30%; mp 97-98 °C; 1H NMR δ 7.12-7.25 (m, 3
H), 6.93 (m, 1 H), 6.18 (s, 1 H), 5.20 (s, 2 H), 4.33 (s, 2 H); IR
1633, 1590, 1563, 1532 cm-1; MS (EI) m/z 269 (M+). Anal.
(C11H9ClFN3) C, H, N.
6-Ch lor o-2-[[(3,4-d ich lor op h en yl)m eth yl]th io]-4-p yr i-
m id in a m in e (37): 31%; mp 171 °C; 1H NMR δ 7.54-7.55 (m,
1 H), 7.35-7.38 (m, 1 H), 7.24-7.28 (m, 1 H), 6.20 (s, 1 H),
5.19 (s, 2 H), 4.26 (s, 2 H); IR 1639, 1571, 1532 cm-1; MS (EI)
m/z 319 (M+). Anal. (C11H8Cl3N3S) C, H, N.
6-Ch lor o-2-[[(3,5-d ibr om op h en yl)m eth yl]th io]-4-p yr i-
m id in a m in e (38): 30%; mp 184-185 °C; 1H NMR δ 7.62-
7.63 (m, 1 H), 7.53 (s, 1 H), 7.48 (m, 1 H), 6.19 (s, 1 H), 5.13 (s,
2 H), 4.36 (s, 2 H); IR 1638, 1563, 1532 cm-1; MS (EI) m/z 407
(M+). Anal. (C11H8Br2ClN3S) C, H, N.
6-Ch lor o-2-[[(3,5-d ich lor op h en yl)m eth yl]th io]-4-p yr i-
m id in a m in e (39): 35%; mp 166-167 °C; 1H NMR δ 7.32 (m,
2 H), 7.23 (s, 1 H), 6.19 (s, 1 H), 5.11 (s, 2 H), 4.25 (s, 2 H); IR
1639, 1563, 1532 cm-1; MS (EI) m/z 319 (M+). Anal. (C11H8-
Cl3N3S) C, H, N.
NMR (DMSO) δ 7.42 (brd s, 2 H), 7.22 (s, 1 H), 7.09 (s, 1 H),
6.19 (s, 1 H), 6.06 (s, 1 H), 4.27 (s, 2 H); IR 1634, 1564, 1532
cm-1; MS (EI) m/z 331 (M+). Anal. (C12H9Cl2N3O2S) C, H, N.
6-Ch lor o-2-[(1-bu t-2-en yl)th io]-4-p yr im id in a m in e (19):
11%; mp 67-69 °C (EtOAc); 1H NMR δ 7.30 (s, 2H), 6.16 (s, 1
H), 5.70 (m, 1 H), 5.56 (m, 1 H), 3.64 (d, J ) 6.9 Hz, 2 H), 1.64
(d, J ) 6.6 Hz, 3 H); IR 1641, 1572, 1533 cm-1; MS (EI) m/z
215 (M+). Anal. (C8H10ClN3S) C, H, N.
6-Ch lor o-2-[[(4-m eth ylp h en yl)m eth yl]th io]-4-p yr im id i-
1
n a m in e (24): 28%; mp 95-96 °C; H NMR δ 7.35 (d, J ) 8.0
Hz, 2 H), 7.13-7.16 (d, J ) 7.9 Hz, 2 H), 6.25 (s, 1 H), 5.09 (s,
2 H), 4.40 (s, 2 H), 2.32 (s, 3 H); IR 1644, 1574, 1535 cm-1; MS
(EI) m/z 265 (M+). Anal. (C12H12ClN3S) C, H, N.
6-Ch lor o-2-[[(3-m eth ylp h en yl)m eth yl]th io]-4-p yr im id i-
n a m in e (25): 29%; mp 97-98 °C (hexane/EtOAc); 1H NMR δ
7.19-7.26 (m, 3 H), 7.07 (m, 1 H), 6.15 (s, 1 H), 4.98 (s, 2 H),
4.32 (s, 2 H), 2.33 (s, 3 H); IR 1629, 1532, 1526 cm-1; MS (EI)
m/z 265 (M+). Anal. (C12H12N3ClS) C, H, N.
6-Ch lor o-2-[[(2-m eth ylp h en yl)m eth yl]th io]-4-p yr im id i-
n a m in e (26): 22%; mp 129-130 °C; 1H NMR δ 7.45-7.48 (m,
1 H), 7.15-7.19 (m, 3 H), 6.21 (s, 1 H), 5.04 (s, 2 H), 4.37 (s, 2
H), 2.38 (s, 3 H); IR 1623, 1566, 1531 cm-1; MS (EI) m/z 265
(M+). Anal. (C12H12ClN3S) C, H, N.
6-Ch lor o-2-[[(1,1′-bip h en yl-4-yl)m eth yl]th io]-4-p yr im -
id in a m in e (27): 9%; mp 162-163 °C (MtBE); 1H NMR δ
7.31-7.59 (m, 9 H), 6.16 (s, 1 H), 4.95 (s, 2 H), 4.39 (s, 2 H);
IR 1684, 1572, 1540 cm-1; MS (EI) m/z 327 (M+). Anal.
(C17H14ClN3S) C, H, N.
6-Ch lor o-2-[[[4-(1,1-dim eth yleth yl)ph en yl]m eth yl]th io]-
4-p yr im id in a m in e (28): 46%; mp 124-125 °C (Et2O/hexane);
1H NMR δ 7.33 (s, 4 H), 6.16 (s, 1 H), 5.05 (s, 2 H), 4.33 (s, 2
H), 1.30 (s, 9 H); IR 1646, 1623, 1572 cm-1; MS (EI) m/z 307
(M+). Anal. (C15H18ClN3S) C, H, N.
6-Ch lor o-2-[[(4-m eth oxyp h en yl)m eth yl]th io]-4-p yr im -
id in a m in e (41). To a solution of 4,6-dihydroxy-2-mercapto-
pyrimidine (40) (40.0 g, 0.278 mol) in 95% EtOH (360 mL) at
22 °C was added 3 N NaOH (97.3 mL, 0.292 mol) followed by
H2O (360 mL). The stirred solution was treated dropwise with
4-methoxybenzyl chloride (45.5 g, 0.292 mol) over a 5-min
period. The reaction mixture was heated at 60 °C for 1.5 h,
stirred at ambient temperature for another 1.5 h, and cooled
in ice bath at 0 °C for 4 h, and the white solid precipitate was
collected. Overnight drying in the vacuum oven at 100 °C
yielded 55.56 g (0.210 mol, 76%) of 4,6-dihydroxy-2-[(4-meth-
oxybenzyl)thio]pyrimidine, sufficiently pure for subsequent
1
reactions: mp 207-208 °C; H NMR (DMSO) δ 11.71 (brd s,
2 H), 7.29 (d, J ) 8.7 Hz, 2 H), 6.81 (d, J ) 8.7 Hz, 2 H), 5.10
(s, 1 H), 4.26 (s, 2 H), 3.67 (s, 3 H); IR 3032, 1641, 1611 cm-1
;
6-Ch lor o-2-[[(4-ca r b om et h oxyp h en yl)m et h yl]t h io]-4-
p yr im id in a m in e (29): 19%; mp 202-203 °C; 1H NMR δ 7.97
(d, J ) 8.3 Hz, 2 H), 7.48-7.51 (d, J ) 8.2 Hz, 2 H), 6.16 (s, 1
H), 4.9 (s, 2 H), 4.37 (s, 2 H), 1.58 (s, 3 H); IR 1715, 1653,
MS (EI) m/z 264 (M+). Anal. (C12H12N2O3S) C, H, N.
To the above (27.93 g, 0.106 mol) was added 2-picoline (16.46
g, 0.177 mol) followed by POCl3 (243 g, 1.59 mol), and the
contents were heated to reflux for 8 h. The excess POCl3 was
removed in vacuo and the thick black slurry poured onto
crushed ice (500 mL). The mixture was stirred at 22 °C to
allow decomposition of the remaining POCl3, then EtOAc was
added, and the contents were stirred overnight. The aqueous
layer was extracted with 3 × EtOAc; then the combined
organics were dried over anhydrous Na2SO4 and concentrated
in vacuo. The residue was chromatographed (hexane/EtOAc,
98:2) to yield 4,6-dichloro-2-[(4-methoxybenzyl)thio]pyrimidine
(20.41 g, 0.0677 mol, 64%): mp 39-42 °C; 1H NMR (CDCl3) δ
7.34 (d, J ) 8.7 Hz, 2 H), 7.01 (s, 1 H), 6.84 (d, J ) 8.7 Hz, 2
1609, 1575, 1538 cm-1; MS (EI) m/z 309 (M+). Anal. (C13H12
-
ClN3O2S) C, H, N.
6-Ch lor o-2-[[(3-ca r b om et h oxyp h en yl)m et h yl]t h io]-4-
p yr im id in a m in e (30): 21%; mp 169-170 °C (EtOAc); 1H
NMR δ 7.68-7.98 (d, J ) 8.4 Hz, 2 H), 7.48-7.51 (d, J ) 8.2
Hz, 2 H), 6.16 (s, 1 H), 4.92 (s, 2 H), 4.37 (s, 2 H), 3.90 (s, 3 H);
IR 1715, 1652, 1572, 1534 cm-1; MS (EI) m/z 309 (M+). Anal.
(C13H12ClN3O2S) C, H, N.
6-Ch lor o-2-[[[3-(tr iflu or om eth yl)p h en yl]m eth yl]th io]-
4-p yr im id in a m in e (31): 19%; mp 95-96 °C; 1H NMR δ 7.72
(s, 1 H), 7.60 (m, 1 H), 7.42-7.4 8 (m, 2H), 6.17 (s, 1 H), 5.02

Pyrimidine Thioethers
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20 3799
H), 4.33 (s, 2 H), 3.78 (s, 3 H); MS (EI) m/z 300 (M+). Anal.
(C12H10Cl2N2OS) C, H, N.
2 H), 3.26 (q, J ) 7.0 Hz, 2 H), 1.17 (t, J ) 7.0 Hz, 3 H), 1.00
(t, J ) 7.0 Hz, 3 H); IR 1654, 1621, 1573, 1531 cm-1; MS (EI)
m/z 274 (M+). Anal. (C10H15N4ClOS) C, H, N.
6-Ch lor o-2-[[(3,4-dih ydr o-2-n aph th alen yl)m eth yl]th io]-
4-p yr im id in a m in e (14): 52%; mp 104-105 °C; 1H NMR δ
7.18-7.06 (m, 3 H), 7.04-7.02 (m, 1 H), 6.55 (s, 1 H), 6.13 (s,
1 H), 5.31 (br s, 2 H), 4.00 (s, 2 H), 2.85 (t, J ) 8.0 Hz, 2 H),
2.42 (t, J ) 8.2 Hz, 2 H); IR 1645, 1573, 1513 cm-1; MS (EI)
m/z 303 (M+). Anal. (C15H14N3ClS) C, H, N.
6-Ch lor o-2-[[(3,4-dih ydr o-1-n aph th alen yl)m eth yl]th io]-
4-p yr im id in a m in e (15): 78%; mp 127-130 °C; 1H NMR δ
7.35 (d, J ) 7.2 Hz, 1 H), 7.21-7.12 (m, 3 H), 6.22 (t, J ) 4.6
Hz, 1 H), 6.14 (s, 1 H), 5.01 (br s, 2 H), 4.23 (s, 2 H), 2.76 (t,
J ) 7.2 Hz, 2 H), 2.33-2.28 (m, 2 H); IR 1643, 1532 cm-1; MS
(EI) m/z 303 (M+). Anal. (C15H14N3ClS) C, H, N.
2-[[(1,3-Ben zod ioxol-5-yl)m eth yl]th io]-6-ch lor o-4-p yr i-
m id in a m in e (17): 59%; mp 148-150 °C; 1H NMR (DMSO) δ
7.32 (br s, 2 H), 6.98 (d, J ) 1.6 Hz, 1 H), 6.89 (dd, J ) 8.0, 1,7
Hz, 1 H), 6.81 (d, J ) 7.9 Hz, 1 H), 6.18 (s, 1 H), 5.97 (s, 2 H),
4.21 (s, 2 H); IR 1640, 1570, 1532, 1500 cm-1; MS (EI) m/z
295 (M+). Anal. (C12H10ClN3O2S) C, H, N.
A solution of the above dichloride (19.55 g, 0.0649 mol) in
warm CH3CN (391 mL) was treated with concentrated NH4-
OH (391 mL) and then heated to 75 °C for 9 h and at 40 °C
overnight. The contents were cooled to room temperature,
filtered, and concentrated in vacuo. The white solid was
extracted with EtOAc, and the organic layer was washed with
a mixture of H2O (50 mL) and saturated NaCl (75 mL). The
combined aqueous layers were extracted with EtOAc and the
combined organics dried over Na2SO4 and concentrated in
vacuo. The crude product was dissolved in refluxing Et2O plus
minimum amount of EtOAc, diluted with hexane, and placed
in the refrigerator to give 41 as a crystalline product (15.0 g,
0.053 mol, 82%): mp 118.5-119.5 °C; 1H NMR (CDCl3) δ 7.26
(d, J ) 8.7 Hz, 2 H), 6.77 (d, J ) 8.7 Hz, 2 H), 6.07 (s, 1 H),
4.93 (br s, 2 H), 4.23 (s, 2 H), 3.72 (s, 3 H); IR 3421, 3302,
3279, 1640, 1619 cm-1; MS (EI) m/z 281 (M+). Anal. (C12H12
-
ClN3OS) C, H, S; N: calcd, 14.95; found, 14.41.
4-Amino-6-chloro-2(1H)-pyrimidinethione,Monomethane-
su lfon a te (42). A suspension of 41 (60.0 g, 0.1993 mol) in
CH2Cl2 (675 mL) at 22 °C was treated with MsOH (153 g, 1.595
mol). After stirring at room temperature until TLC indicated
consumption of starting materials (3.5 h), the wine-red reaction
mixture was diluted dropwise with Et2O with periodic seeding
during the initial addition phase until a suspended solid began
to form in generous amount. The rate of addition was then
gradually accelerated until a total of 3 L had been added over
a period of several hours. When allowed to stir overnight, the
suspended product seems to form a more granular solid of
higher purity than if collected immediately after the addition
of Et2O. The yellow solid was collected at room temperature
on a filter and washed with Et2O. The crude product was
suspended in refluxing CH2Cl2 (480 mL) to which was added
MeOH in portions until nearly all material dissolved (ca. 270
mL). The hot mixture was filtered and the warm filtrate
diluted, initially dropwise, with Et2O with periodic seeding
until a significant amount of white suspended solid was noted.
Then the addition of Et2O was accelerated until a total of 3 L
was added over a period of 3 h. The pale-yellow solid was
collected at room temperature, washed with Et2O, and dried
in a vacuum oven at 50 °C to obtain 49.2 g (0.191 mol, 96%) of
(E)-N,N-Dim eth yl-4-[(4-a m in o-6-ch lor o-2-p yr im id in yl)-
th io]-2-bu ten a m id e (21): 53%; mp 173-176 °C (hexane/
1
EtOAc); H NMR (DMSO) δ 7.34 (br s, 2 H), 6.68-6.57 (m, 2
H), 6.19 (s, 1 H), 3.82-3.80 (m, 2 H), 3.01 (s, 3 H), 2.84 (s, 3
H), 2.80 (t, J ) 7.1 Hz, 2 H); IR 1661, 1575, 1530 cm-1; MS
(EI) m/z 272 (M+). Anal. (C10H13ClN4OS) C, H, N.
(E)-N,N-Diet h yl-4-[(4-a m in o-6-ch lor o-2-p yr im id in yl)-
th io]-2-bu ten a m id e (22): 45%; mp 143-145 °C (hexane/
1
EtOAc); H NMR (DMSO) δ 7.34 (br s, 2 H), 6.65-6.56 (m, 2
H), 6.19 (s, 1 H), 3.81 (d, J ) 6.1 Hz, 2 H), 3.35-3.27 (m, 4 H),
1.08-0.99 (m, 6 H); IR 1660, 1605, 1574, 1530 cm-1; MS (EI)
m/z 300 (M+). Anal. (C12H17N4ClOS) C, H, N.
(E)-N-Eth yl-4-[(4-a m in o-6-ch lor o-2-p yr im id in yl)th io]-
2-bu ten a m id e (23): 11%; mp 160-161 °C (hexane/EtOAc);
1H NMR (DMSO) δ 7.98 (m, 1 H), 7.31 (br s, 2 H), 6.62 (dt, J
) 15.2, 6.8 Hz, 1 H), 6.19 (s, 1 H), 6.07 (d, J ) 15.2 Hz, 1 H),
3.79 (d, J ) 6.9 Hz, 2 H), 3.19-3.07 (m, 2 H), 1.01 (t, J ) 7.2
Hz, 3 H); IR 1663, 1644, 1614, 1578, 1558, 1524 cm-1; MS (EI)
m/z 327 (M+). Anal. (C10H13ClN4OS) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of Dich lor op y-
r im id in es. 4,6-Dich lor o-2-[(p h en ylm eth yl)th io]p yr im i-
d in e (43). Thiobarbituric acid (5.22 g, 36.2 mmol) in EtOH
(52 mL) was treated with 3.25 M NaOH (11.1 mL, 36.2 mmol)
and then heated to reflux for 30 min. Bn-Br (4.3 mL, 36 mmol)
was added, and reflux continued for an additional 2 h. The
resultant white solid was collected, washed with cold H2O and
EtOH, and then dried to yield 2-[(phenylmethyl)thio]barbituric
acid as a white solid: 6.5 g (27 mmol, 77%); mp > 320 °C; 1H
NMR (DMSO-d6) δ 7.45-7.36 (m, 2 H), 7.34-7.21 (m, 3 H),
5.18 (s, 1 H), 4.38 (s, 2 H).
1
analytically pure 42: mp 166.5-167 °C; H NMR (DMSO) δ
6.34 (s, 1 H), 2.46 (s, 3 H); IR 3146, 1704, 1677, 1669 cm-1
;
MS (EI) m/z 161 (M+). Anal. (C5H8ClN3O3S2) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of 2-(Su bstitu ted
th io)ch lor oa m in op yr im id in e Der iva tives. Meth od B.
(E)-4-[(4-Am in o-6-ch lor o-2-p yr im id in yl)t h io]-2-b u t en o-
ic Acid Meth yl Ester (20). Compound 42 (300 mg, 1.16
mmol) was dissolved in 3.25 M NaOH (2 mL) and EtOH (1
mL) and then treated with methyl 4-bromocrotonate (0.16 mL,
1.40 mmol). After 30 min, the solid was dissolved in CH2Cl2
(50 mL) and water (50 mL). The organic phase was washed
with H2O (30 mL) and saturated NaCl (30 mL), dried with
Na2SO4, and concentrated in vacuo. The crude product was
purified by chromatography (hexane/EtOAc, 75:25) to give 20
as white granules: 119 mg (0.46 mmol, 40%); mp 146-149 °C
(hexane/EtOAc); 1H NMR δ 7.08-6.97 (m, 1 H), 6.17 (s, 1 H),
6.04-6.01 (m, 1 H), 5.02 (br s, 2 H), 3.85 (dd, J ) 7.1, 1.3 Hz,
2 H), 3.73 (s, 3 H); IR 1649, 1572, 1531 cm-1; MS (EI) m/z 259
(M+). Anal. (C9H10N3ClSO2) C, H, N.
2-[(4-Am in o-6-ch lor o-2-p yr im id in yl)t h io]a cet ic a cid
(9): 69%; mp 173-176 °C (hexane/EtOAc); 1H NMR (DMSO)
δ 12.65 (s, 1 H), 7.29 (s, 2 H), 6.17 (s, 1 H), 3.85 (s, 1 H); IR
1726, 1663, 1576, 1529 cm-1; MS (EI) m/z 219 (M+). Anal.
(C6H6ClN3O2S) C, H, N.
3-[(4-Am in o-6-ch lor o-2-pyr im idin yl)th io]pr opan oic acid
m eth yl ester (10): 23%; mp 112-114 °C; 1H NMR δ 6.17 (s,
1 H), 5.28 (br s, 2 H), 3.71 (s, 3 H), 3.32 (t, J ) 7.1 Hz, 2 H),
2.80 (t, J ) 7.1 Hz, 2 H); IR 1719, 1651, 1574, 1532 cm-1; MS
(EI) m/z 247 (M+). Anal. (C8H10N3ClO2S) C, H, N.
The crude (5.95 g, 25.4 mmol) was treated with POCl3 (26
mL) and heated to reflux for 2 h; then excess POCl3 was
removed in vacuo. The hot residue was poured onto ice, the
pH was adjusted to 7 with NaOH, and then the aqueous phase
was extracted 3 × EtOAc. The organics were washed with 3
× NaOH and 2 × saturated NaCl, dried with MgSO4, and
concentrated in vacuo. The crude was chromatographed
(toluene/hexane, 1:1) to give 43 as an irritating yellow oil: 5.0
1
g (18 mmol, 73%); H NMR δ 7.45-7.41 (m, 2 H), 7.35-7.23
(m, 3 H), 7.03 (s, 1 H), 4.38 (s, 2 H); IR 1539, 1530 cm-1; MS
(EI) m/z 272 (M+).
4,6-Dich lor o-2-[(2-n a p h t h a len ylm et h yl)t h io]p yr im i-
d in e (44): 54%; mp 113-114 °C; 1H NMR δ 7.92 (s, 1 H), 7.80
(m, 3 H), 7.52 (m, 1 H), 7.48-7.45 (m, 2 H), 7.03 (s, 1 H), 4.54
(s, 2 H); IR 1542, 1532 cm-1; MS (EI) m/z 322 (M+). Anal.
(C15H10N2Cl2S) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of (Su bstitu ted
a m in o)p yr im id in es. 6-Ch lor o-2-[(p h en ylm eth yl)th io]-N-
p r op yl-4-p yr im id in a m in e (45). Compound 43 (0.23 g, 0.87
mmol) was dissolved in CH2Cl2 (2 mL) and treated with Et3N
(0.18 mL, 1.3 mmol) and n-propylamine (0.14 mL, 1.7 mmol).
The mixture was stirred at room temperature for 20 h, then
washed with 2 × saturated NaHCO3, dried with MgSO4, and
N,N-Dieth yl-2-[(4-a m in o-6-ch lor o-2-p yr im id in yl)th io]-
a ceta m id e (11): 78%; mp 156-157 °C; 1H NMR (DMSO) δ
7.25 (br s, 2 H), 6.17 (s, 1 H), 4.00 (s, 2 H), 3.40 (q, J ) 7.0 Hz,

3800 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20
Nugent et al.
concentrated in vacuo. The residue was chromatographed
(hexane/EtOAc, 10:1) to give 45 as a colorless oil, 0.23 g (0.79
mmol, 91%), which solidified upon standing: mp 67-68 °C;
1H NMR δ 7.42-7.40 (m, 2 H), 7.32-7.20 (m, 3 H), 6.03 (s, 1
H), 5.04 (brd s, 1 H), 4.35 (s, 2 H), 3.23 (m, 2 H), 1.61 (hex, 2
H), 0.97 (t, J ) 7.4 Hz, 3H); IR 1574, 1538 cm-1; MS (EI) m/z
293 (M+). Anal. (C14H16ClN3S) C, H, N.
6-Ch lor o-2-[(p h en ylm eth yl)th io]-N-(3-h yd r oxyp r op yl)-
4-p yr im id in a m in e (46): 87%; mp 103-104 °C; 1H NMR δ
7.43-7.41 (m, 2H), 7.32-7.22 (m, 3H), 6.06 (s, 1H), 5.34 (brd
s, 1H), 4.36 (s, 2H), 3.73 (t, 2H), 3.50 (brd s, 2H), 1.81 (m, 2H);
IR 1608, 1601, 1572 cm-1; MS (EI) m/z 309 (M+). Anal.
(C14H16ClN3OS) C, H, N.
6-Ch lor o-2-[(p h en ylm eth yl)th io]-N-cycloh exyl-4-p yr i-
m id in a m in e (47): 82%; 1H NMR δ 7.43-7.40 (m, 2H), 7.32-
7.20 (m, 3 H), 6.00 (s, 1 H), 4.96 (brd s, 1 H), 4.34 (s, 2 H),
3.75-3.19 (brd, 1 H), 1.99-1.93 (m, 2 H), 1.83-1.60 (m, 3 H),
1.43-1.15 (m, 5 H); IR 1567, 1537 cm-1; MS (EI) m/z 333 (M+).
Anal. (C17H20ClN3S) C, H, N.
6-Ch lor o-2-[(p h en ylm eth yl)th io]-4(1H)-p yr im id in on e
h yd r a zon e (48): 29%; mp 136-138 °C (EtOH/H2O); 1H NMR
δ 7.41-7.39 (m, 2 H), 7.32-7.23 (m, 3 H), 6.56 (m, 1 H), 6.48
(brd s, 1 H), 4.34 (s, 2 H), 3.21 (m, 1 H); IR 1652, 1575, 1551
cm-1; MS (EI) m/z 236 (M+). Anal. (C11H11ClN4S) C, H, N.
4-Ch lor o-2-[(p h en ylm eth yl)th io]-6-(1-p yr r olid in yl)p y-
r im id in e (49): 43%; mp 80-81 °C (cyclohexane);1H NMR δ
7.43-7.40 (m, 2 H), 7.31-7.22 (m, 3 H), 5.99 (s, 1 H), 4.36 (s,
2 H), 3.60 (m, 2 H), 3.28 (m, 2 H), 2.10-1.87 (m, 4 H); IR 1585,
1580, 1540 cm-1; MS (EI) m/z 305 (M+). Anal. (C15H16N3ClS)
C, H, N.
4-Ch lor o-2-[(p h en ylm eth yl)th io]-6-p ip er id in ylp yr im i-
d in e (50): 64%; mp 85-86 °C (cyclohexane);1H NMR δ 7.42-
7.40 (m, 2 H), 7.32-7.20 (m, 3 H), 6.18 (s, 1 H), 4.34 (s, 2 H),
3.57 (m, 4 H), 1.70-1.64 (m, 2 H), 1.62-1.54 (m, 4 H); IR 1572,
1533 cm-1; MS (EI) m/z 319 (M+). Anal. (C16H18ClN3S) C, H,
N.
4-Ch lor o-6-im id a zolyl-2-[(n a p h t h a len ylm et h yl)t h io]-
p yr im id in e (51): 34%; mp 115-117 °C; 1H NMR δ 8.45 (s, 1
H), 7.92 (s, 1 H), 7.83-7.79 (m, 3 H), 7.57-7.53 (m, 2 H), 7.49-
7.44 (m, 2 H), 7.22 (s, 1 H), 6.99 (s, 1 H), 4.58 (s, 2 H); IR
1560, 1544, 1520, 1508 cm-1; MS (EI) m/z 352 (M+). Anal.
(C18H13ClN4S‚0.25H2O) C, H, N.
H), 5.08 (s, 1 H), 4.41 (brd s, 2 H), 4.37 (s, 2 H), 3.41 (m, 4 H),
1.95 (m, 4 H); IR 1633, 1584, 1545 cm-1; MS (EI) m/z 286 (M+).
Anal. (C15H18N4S) C, H, N.
6-Meth yl-2-[(ph en ylm eth yl)th io]-4-pyr im idin am in e (55).
2-(Benzylthio)-4-chloro-6-methylpyrimidine20 (0.50 g, 2.0 mmol)
was dissolved in NH3/MeOH (2 mL) and then heated in a
sealed vial to 100 °C for 24 h. The mixture was cooled and
concentrated with a stream of N2; then the residue was
dissolved in EtOAc and washed 3 × H2O. The organic layer
was dried with MgSO4 and concentrated in vacuo. The brown
residue was chromatographed (hexane/EtOAc, 3:1) to yield
1
55: 152 mg (0.657 mmol, 33%); mp 107-108 °C; H NMR δ
7.40 (m, 2 H), 7.27 (m, 3 H), 6.05 (s, 1 H), 5.07 (brd s, 2 H),
4.37 (s, 2 H), 2.31 (s, 3 H); IR 1626, 1587, 1583, 1537 cm-1
;
MS (EI) m/z 231 (M+). Anal. (C12H13N3S) C, H, N.
4-Ch lor o-2-[(2-n a p h t h a len ylm et h yl)t h io]p yr im id in e
(56). 2-Thiouracil (2.56 g, 20.0 mmol) suspended in H2O (20
mL) was treated with NaOH (0.88 g, 20 mmol) and then stirred
until dissolved. The reaction was diluted with EtOH (20 mL),
treated with 2-(bromomethyl)naphthalene (4.6 g, 21 mmol),
and then heated at reflux for 3 h. The reaction was cooled
and the precipitate collected. The hydroxypyrimidine (3.48 g,
12.9 mmol) was heated in POCl3 (16 mL) overnight at reflux.
Excess reagent was removed at reduced pressure and the
residue poured onto ice. The product was extracted with
EtOAc, washed with saturated NaCl, dried with MgSO4, and
concentrated in vacuo. The brown residue was chromato-
graphed (hexane/EtOAc, 9:1) to yield 56: 2.97 g (10.4 mmol,
1
52%); mp 76-77 °C; H NMR (DMSO-d6) δ 8.64 (d, J ) 5.3
Hz, 1 H), 7.97 (s, 1 H), 7.88 (m, 3 H), 7.6-7.45 (m, 3 H), 7.43
(d, J ) 5.2 Hz, 1 H) 4.59 (s, 2 H); IR 1545, 1532 cm-1; MS (EI)
m/z 286 (M+). Anal. (C15H11ClN2S) C, H, N.
2-[(2-Naph th alen ylm eth yl)th io]-4-pyr im idin am in e (57).
2-Thiocytosine (505 mg, 3.97 mmol) was dissolved in EtOH
(1.3 mL) and 3.25 M NaOH (1.3 mL, 4.2 mmol) and stirred for
20 min. 2-(Bromomethyl)naphthalene (877 mg, 3.97 mmol)
was added, and the reaction was heated to reflux for 30 min.
After cooling, the reaction was concentrated in vacuo, and the
residue was dissolved in EtOAc, washed with saturated
NaHCO3 and saturated NaCl, dried with MgSO4, and concen-
trated in vacuo. The crude was chromatographed (hexane/
EtOAc, 9:1) to yield 57: 0.24 g (0.91 mmol, 23%); mp 115-
116 °C (cyclohexane);1H NMR (DMSO) δ 7.93 (m, 2 H), 7.85
(m, 3 H), 7.55 (m, 1 H), 7.48 (m, 2 H), 7.00 (brd s, 2 H), 6.16
(d, J ) 5.8 Hz, 1 H), 4.46 (s, 2 H); IR 1649, 1638, 1611, 1577,
1542 cm-1; MS (EI) m/z 267 (M+). Anal. (C15H13N3S) C, H,
N.
N-[6-Ch lor o-2-[(2-n a p h th a len ylm eth yl)th io]-4-p yr im -
id in yl]a ceta m id e (52). Compound 5 (0.30 g, 1.0 mmol) was
dissolved in EtOAc (5 mL) and treated with NaOMe (25% in
MeOH, 0.23 mL, 1.0 mmol). After stirring for 3 h, the reaction
was quenched with 1 M HCl, washed with H2O and saturated
NaCl, dried with MgSO4, and concentrated in vacuo to give
52 as white crystals: 123 mg (0.358 mmol, 36%); mp 179-
2-[(P h en ylm et h yl)t h io]-6-(t r iflu or om et h yl)-4-p yr im i-
d in ol (58). Ethyl trifluoroacetoacetate (8.84 g, 48.0 mmol)
and thiourea (3.8 g, 50 mmol) were combined in absolute EtOH
(50 mL), treated with 25% NaOMe/MeOH (12.0 mL, 52.5
mmol), and then heated to reflux. After 4 h, the reaction was
concentrated nearly to dryness, acidified with 1 N HCl (53 mL),
and filtered. The solid was washed with water and dried.
Crude solid (1.47 g, 7.50 mmol) was dissolved in EtOH (2.5
mL) and 3.25 N NaOH (2.3 mL, 7.5 mmol), treated with a
solution of 2-(bromomethyl)naphthalene (1.65 g, 7.50 mmol)
in EtOH (5 mL), and then refluxed for 1 h. The cooled reaction
mixture was filtered and the crude product purified by
recrystallization from EtOH to yield 58: 1.55 g (4.62 mmol,
1
180 °C (EtOAc); H NMR 7.87 (s, 2 H), 7.80 (m, 3 H), 7.55-
7.45 (m, 3 H), 4.52 (s, 2 H), 2.21 (s, 3 H); IR 1696, 1582, 1552,
1511 cm-1; MS (EI) m/z 343 (M+). Anal. (C17H14ClN3OS) C,
H, N.
6-Ch lor o-2-[(2-n a p h th a len ylm eth yl)th io]-4-p h en ylp y-
r im id in e (53). 4-Chloro-2-[(naphthalenylmethyl)thio]-6-phen-
ylpyrimidine19 (0.34 g, 1.0 mmol) and POCl3 (3 mL) were
heated at reflux for 2 h; then excess POCl3 was distilled. The
residue was poured onto ice, extracted with EtOAc, washed
with saturated NaHCO3 and saturated NaCl, dried with
MgSO4, and concentrated in vacuo to yield 53: 129 mg (0.356
mmol, 36%); mp 93-94 °C (toluene/hexane); 1H NMR (DMSO)
δ 8.23 (m, 1 H), 8.03 (s, 1 H), 8.00 (s, 1 H), 7.90 (m, 2 H), 7.85
(m, 1 H), 7.7-7.45 (m, 6 H), 4.69 (s, 2 H); IR 1599, 1548, 1522
cm-1; MS (EI) m/z 358 (M+). Anal. (C21H15ClN2S) C, H, N.
2-[(P h e n y lm e t h y l)t h io ]-6-p y r r o lid in o -4-p y r im id i-
n a m in e (54). Compound 2 (0.20 g, 0.80 mmol) in THF (1.6
mL) was treated with pyrrolidine (0.20 mL, 2.4 mmol) and
heated to reflux for 60 h. The mixture was cooled and
concentrated with a stream of nitrogen; then the residue was
dissolved in CH2Cl2 and washed 3 × H2O. The organic layer
was dried with MgSO4 and concentrated in vacuo. The brown
residue was chromatographed (hexane/EtOAc, 2:1) to yield 54
as tan needles: 0.11 g (0.37 mmol, 47%); mp 143-144 °C
1
10%); mp 211-212 °C; H NMR (DMSO) δ 7.94 (s, 1 H), 7.86
(d, J ) 8.4 Hz, 2 H), 7.80 (m, 1 H), 7.55 (d, J ) 8.4 Hz, 1 H),
7.50 (m, 2 H), 6.61 (s, 1 H), 4.56 (s, 2 H); IR 1676, 1553, 1419
cm-1; MS (EI) m/z 336 (M+). Anal. (C16H11F3N2OS) C, H, N.
4-Ch lor o-2-[(2-n a p h th a len ylm eth yl)th io]-6-(tr iflu or o-
m eth yl)p yr im id in e (59). Compound 58 (1.47 g, 4.37 mmol)
and POCl3 (5 mL) were heated to reflux for 2 h, and the excess
POCl3 was distilled. The residue was poured onto ice and
extracted 3 × EtOAc. The organics were then washed with
H2O and saturated NaCl, dried with MgSO4, and then con-
centrated in vacuo. The crude product was then purified by
recrystallization from hexane: 910 mg (2.56 mmol, 58%); mp
1
65-66 °C; H NMR δ 7.95 (s, 1 H), 7.81 (d, J ) 8.7 Hz, 2 H),
1
(toluene/heptane); H NMR δ 7.40 (d, 2 H), 7.29-7.20 (m, 3
7.81(s, 1 H), 7.54 (m, 1 H), 7.47 (m, 2 H), 7.27 (s, 1 H), 4.57 (s,

Pyrimidine Thioethers
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20 3801
2 H); IR 1564, 1552, 1541 cm-1; MS (EI) m/z 354 (M+). Anal.
(C16H10ClF3N2S) C, H, N.
then dried: 3.03 g (9.70 mmol, 97%); 1H NMR (DMSO) δ 8.10
(s, 1 H), 7.83 (m, 3 H), 7.60 (dd, J ) 1.8, 8.5 Hz, 1 H), 7.48 (m,
2 H), 6.63 (s, 1 H), 4.59 (s, 2 H).
2-[(2-Na p h th a len ylm eth yl)th io]-6-(tr iflu or om eth yl)-4-
p yr im id in a m in e (60). Compound 59 (733 mg, 2.06 mmol)
was treated with NH3/MeOH (6 mL) at 0 °C for 1 h, then
warmed to room temperature, and stirred for 2.5 h. The
reaction was concentrated, and the crude products were
purified by chromatography (hexane/EtOAc, 6:1, 1:1) to give
60: 70 mg (0.21 mmol, 10%); mp 144-145 °C; 1H NMR δ 7.91
(s, 1 H), 7.77 (m, 3 H), 7.53 (dd, J ) 1.7, 8.5 Hz, 1 H), 7.44 (m,
2 H), 6.41 (s, 1 H), 5.14 (s, 2 H), 4.52 (s, 2 H); IR 1642, 1547
cm-1; MS (EI) m/z 335 (M+). Anal. (C16H12F3N3S) C, H, N.
6-(Dieth oxym eth yl)-2-[(2-n a p h th a len ylm eth yl)th io]-4-
p yr im id in ol (61). Ethyl diethoxyacetate (10.4 mL, 60.0
mmol) and EtOAc (9.0 mL, 90 mmol) were heated to 80-90
°C and then treated with Na (1.44 g, 60 mmol) in small
portions. After 2 h, EtOAc (9.0 mL, 90 mmol) and Na (1.44 g,
60 mmol) were added, and heating was maintained for an
additional 3 h. The red oily mass was poured onto water (15
mL), acidified with 10% HCl, and extracted 3 × methyl tert-
butyl ether. The organics were washed with 3 × saturated
NaHCO3 and saturated NaCl, dried with MgSO4, and then
concentrated in vacuo. The crude product was dried overnight
in the vacuum oven at 70 °C to remove any ethyl acetoacetate
that may have been produced. The crude keto ester was
treated with thiourea (4.57 g, 60 mmol), EtOH (45 mL), and
25% NaOMe (13 mL, 57 mmol) and heated to reflux for 4 h.
The reaction was diluted with water (50 mL), treated with
2-(bromomethyl)naphthalene (12.0 g, 54.3 mmol), and then
stirred warm for 1 h. The white solid was diluted with H2O,
filtered, and then recrystallized from EtOAc to give 61: 11.2
g (30.1 mmol, 50%); mp 163-164 °C; 1H NMR (DMSO) δ 7.95
(s, 1 H), 7.85 (m, 3 H), 7.58 (dd, J ) 1.7, 8.4 Hz, 1 H), 7.48 (m,
2 H), 6.14 (s, 1 H), 5.21 (s, 1 H), 4.56 (s, 2 H), 3.58 (m, 4 H),
1.13 (t, J ) 7.1 Hz, 6 H); IR 1664, 1549 cm-1; MS (EI) m/z 370
(M+);
The crude acid (2.50 g, 8.00 mmol) and CDI (1.9 g, 12 mmol)
were stirred in DMF (30 mL) for 30 min. EtOH (8 mL) was
added, and the mixture stirred for 1.5 h. The reaction was
poured onto H2O (200 mL) and stirred for 20 min; then the
product was collected by filtration and dried: 2.37 g (7.05
1
mmol, 88%); H NMR (DMSO) δ 8.06 (s, 1 H), 7.83 (m, 3 H),
7.63 (d, J ) 8.4 Hz, 1 H), 7.48 (m, 2 H), 6.65 (s, 1 H), 4.58 (s,
2 H), 4.36 (q, J ) 7.1 Hz, 2 H), 1.35 (t, J ) 7.1 Hz, 3 H).
The crude ester (2.32 g, 6.81 mmol), POCl3 (7 mL), and
2-picoline (0.7 mL) were stirred at room temperature for 3 h
and then poured onto ice. The precipitate was collected and
stirred with NH4OH for 15 min. The tan solid was collected
and recrystallized from MeOH to give 66: 1.72 g (4.79 mmol,
70%) mp 95-96 °C; 1H NMR δ 8.00 (s, 1 H), 7.81 (m, 3 H),
7.61 (s, 1 H), 7.59 (m, 1 H), 7.46 (m, 2 H), 4.59 (s, 2 H), 4.49
(q, J ) 7.1 Hz, 2 H), 1.45 (t, J ) 7.1 Hz, 3 H); IR 1729, 1540
cm-1; MS (EI) m/z 358 (M+). Anal. (C18H15ClN2O2S) C, H, N.
6-Am in o-2-[(2-n a p h th a len ylm eth yl)th io]-4-pyr im id in e-
ca r boxylic Acid Eth yl Ester (67). 66 (1.11 g, 3.08 mmol)
in DMF (9 mL) was treated with NaN3 (0.60 g, 9.23 mmol)
and stirred for 24 h. The yellow solution was concentrated in
vacuo to dryness and then diluted with EtOAc. The solution
was filtered through Celite, washed with H2O and saturated
NaCl, dried with MgSO4, and then concentrated in vacuo to
yield crude azide: 1.20 g. The crude azide in EtOAc (45 mL)
and EtOH (20 mL) was treated with SnCl2 (3.8 g, 17 mmol).
After 15 min, the reaction was poured onto ice/saturated
NaHCO3, and the resulting tin salts were filtered through
Celite. The filtrate was extracted 2 × EtOAc, and the organics
were washed with saturated NaCl, dried with MgSO4, and
then concentrated in vacuo. The crude product was then
purified by trituration with methyl tert-butyl ether to yield
67: 646 mg (1.90 mmol, 62% for 2 steps); mp 188-189 °C; 1H
NMR (DMSO) δ 8.22 (s, 1 H), 8.02 (s, 1 H), 7.83 (m, 3 H), 7.60
(dd, J ) 1.1, 8.3 Hz, 1 H), 7.48 (m, 2 H), 7.27 (s, 2 H), 6.76 (s,
1 H), 4.47 (s, 2 H), 4.32 (q, J ) 7.1 Hz, 2 H), 1.31 (t, J ) 7.1
Hz, 3 H); IR 1703, 1648, 1593, 1540 cm-1; MS (EI) m/z 339
(M+). Anal. (C18H17N3O2S) C, H, N.
6-Ch lor o-2-[(2-n aph th alen ylm eth yl)th io]-4-pyr im idin e-
ca r bon itr ile (63). Compound 61 (1.85 g, 5.0 mmol) and 50%
HOAc (20 mL) were refluxed for 2 h and then taken to dryness
under a stream of nitrogen. The crude aldehyde was sus-
pended in hot EtOH (25 mL), treated with NaOAc (2.8 g) and
then with a solution of NH2OH‚HCl (1.85 g) in H2O (25 mL),
and then refluxed for 1 h. The crude product, 62, was isolated
by filtration: 1.204 g (3.87 mmol, 77%).
6-Ch lor o-2-[(ph en ylm eth yl)oxy]-4-pyr im idin am in e (69).
NaH (50% in oil, 61 mg, 1.2 mmol) and THF (3.6 mL) were
slurried together and cooled to 0 °C. BnOH (0.12 mL, 1.2
mmol) was added and the solution warmed to 22 °C for 30
min. The reaction mixture was recooled to 0 °C and 68 (198
mg, 1.2 mmol) added. The solution was stirred for 18 h at 22
°C, then quenched with saturated NH4Cl, and concentrated
in vacuo. The residue was dissolved in EtOAc, washed with
2 × saturated NaHCO3 and 1 × saturated NaCl, dried with
MgSO4, and concentrated in vacuo. The crude product was
chromatographed (hexane/EtOAc, 4:1) to yield 69: 101 mg
(0.430 mmol, 36%); mp 114-115 °C; 1H NMR δ 7.45 (m, 2 H),
7.34 (m, 3 H), 6.15 (s, 1 H), 5.36 (s, 2 H), 5.00 (brd s, 2 H); IR
1642, 1632, 1583, 1551 cm-1; MS (EI) m/z 235 (M+). Anal.
(C11H10ClN3O) C, H, N.
62 (720 mg, 2.31 mmol), POCl3 (3 mL), and 2-picoline (0.5
mL) were heated to reflux for 2 h, then poured onto ice, and
extracted 2 × EtOAc. The organics were washed with 2 ×
saturated NaHCO3, dried with MgSO4, and then concentrated
in vacuo. The crude product was purified by chromatography
(hexane/EtOAc, 95:5) to give 63: 322 mg (1.03 mmol, 45%);
1
mp 120-121 °C; H NMR δ 7.93 (s, 1 H), 7.82 (d, J ) 4.3 Hz,
3 H), 7.50 (m, 3 H), 7.27 (s, 1 H), 4.55 (s, 2 H); IR 1551, 1527,
1509 cm-1; MS (EI) m/z 311 (M+). Anal. (C16H10ClN3S) C, H,
N.
6-Am in o-2-[(2-n a p h th a len ylm eth yl)th io]-4-p yr im idin e-
ca r bon itr ile (64). Compound 63 (0.30 g, 0.96 mmol) was
treated with 1:1 THF/NH4OH (10 mL) and stirred at room
temperature for 6 h. The reaction was diluted with EtOAc,
washed with water and saturated NaCl, dried with MgSO4,
and concentrated in vacuo. The crude product was purified
by recrystallization from toluene: 155 mg (0.530 mmol, 55%);
6-Ch lor o-2-[[(3-m eth ylph en yl)m eth yl]oxy]-4-pyr im idin -
1
a m in e (70): 45%; mp 85-87 °C; H NMR δ 7.27-7.23 (m, 3
H), 7.16-7.11 (m, 1 H), 6.18 (s, 1 H), 5.48 (brd s, 2 H), 5.33 (s,
2 H), 2.35 (s, 3 H); IR 1641, 1586, 1552 cm-1; MS (EI) m/z 249
(M+). Anal. (C12H12ClN3O) C, H, N.
1
6-Ch lor o-2-[(1-n a p h th a len ylm eth yl)oxy]-4-p yr im id in -
a m in e (71): 19%; mp 160-161 °C; 1H NMR δ 8.11 (d, J ) 7.8
Hz, 1 H), 7.89-7.82 (m, 2 H), 7.65 (d, J ) 7.0 Hz, 1 H), 7.55-
7.42 (m, 3 H), 6.14 (s, 1 H), 5.82 (s, 2 H), 5.01 (brd s, 2 H); IR
1582, 1550, 1511 cm-1; MS (EI) m/z 285 (M+). Anal. (C15H12N3-
ClO) C, H, N.
6-Ch lor o-2-[(2-n a p h th a len ylm eth yl)oxy]-4-p yr im id in -
a m in e (72): 11%; mp 130-131 °C (heptane/toluene); 1H NMR
δ 7.92 (s, 1 H), 7.85-7.82 (m, 3 H), 7.56-7.46 (m, 3 H), 6.15
(s, 1 H), 5.52 (s, 2 H), 5.01 (brd s, 2 H); IR 1632, 1578, 1545
cm-1; MS (EI) m/z 285 (M+). Anal. (C15H12N3ClO) C, H, N.
6-Ch lor o-2-[(2-n a p h t h a len ylm et h yl)a m in o]-4-p yr im -
id in a m in e (74). Compound 73 (0.25 g, 1.5 mmol) was
mp 154-155 °C; H NMR δ 7.89 (s, 1 H), 7.80 (m, 3 H), 7.48
(m, 3 H), 6.45 (s, 1 H), 5.15 (s, 2 H), 4.51 (s, 2 H); IR 3168 (b),
1650, 1642, 1581, 1534 cm-1; MS (EI) m/z 292 (M+). Anal.
(C16H12N4S) C, H, N.
6-Ch lor o-2-[(2-n aph th alen ylm eth yl)th io]-4-pyr im idin e-
ca r boxylic Acid Eth yl Ester (66). Thioorotic acid, 65 (1.72
g, 10.0 mmol), was suspended in 80% EtOH (20 mL) and then
treated with NaOH (0.88 g, 22 mmol) and H2O (10 mL). The
suspension was stirred for 5 min, then 2-(bromomethyl)-
naphthalene (2.2 g, 10 mmol) was added, and the reaction was
heated to reflux for 2 h. While still warm, the reaction was
quenched with 1 N HCl (11 mL) to give a white precipitate.
After cooling, the solid was collected, washed with water, and

3802 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 20
Nugent et al.
dissolved in CH2Cl2 (4 mL), cooled to 0 °C, and treated with
NaH (50% in oil, 72 mg, 1.5 mmol). After stirring for 30 min
at 0 °C, 2-(bromomethyl)naphthalene (0.49 g, 2.2 mmol) was
added and the mixture stirred at room temperature for 72 h
and then at reflux for 10 h. The mixture was cooled, diluted
with CH2Cl2, and quenched with saturated NH4Cl. The
organic layer was washed with 2 × H2O, dried with MgSO4,
and concentrated to an orange solid. The material was
chromatographed (hexane/EtOAc, 15:1) to give a dichloropy-
rimidine as a fluffy white solid: 191 mg (0.630 mmol, 42%);
mp 155-156 °C (heptane).
This pyrimidine (97 mg, 0.32 mmol) was added to saturated
NH3 in MeOH (4 mL), and the resultant solution was heated
to 110 °C for 24 h in a sealed vial. After cooling to room
temperature, the solvent was removed in a stream of N2 and
the residue partitioned between EtOAc and H2O. The organic
portion was washed with 2 × H2O and 1 × saturated NaCl,
dried with MgSO4, and concentrated in vacuo. The residue
was chromatographed (EtOAc/hexane, 1:1) to give 74 as a
white solid: 76 mg (0.27 mmol, 83%); mp 134-135 °C; 1H NMR
δ 7.83-7.74 (m, 5 H), 7.48-7.41 (m, 3 H), 5.84 (s, 1 H), 4.75
(brd s, 2 H), 4.73 (s, 2 H); IR 1646, 1622, 1594, 1572, 1528
cm-1; MS (EI) m/z 284 (M+). Anal. (C15H13N4Cl) C, H, N.
6-Ch lor o-2-[2-(2-n aph th yl)eth yl]-4-pyr im idin am in e (78).
2-Naphthylethanol (7.8 g, 45 mmol) and Et3N (6.6 mL, 47
mmol) in THF (75 mL) at 0 °C were treated dropwise with
MsCl (3.6 mL, 47 mmol), then warmed to 22 °C, and stirred
for 3 h. The reaction was diluted with EtOAc, washed with 2
× 1 M HCl, 1 × H2O, 2 × saturated NaHCO3, and 1 ×
saturated NaCl, dried with Na2SO4, and concentrated in vacuo
to give the mesylate as a slightly pink solid: 11.8 g (45.0 mmol,
100%); 1H NMR δ 7.83-7.79 (m, 3 H), 7.70 (s, 1 H), 7.51-7.44
(m, 2 H), 7.35 (m, 1 H), 4.51 (t, J ) 6.9 Hz, 2 H), 3.22 (t, J )
6.8 Hz, 2 H), 2.83 (s, 3 H).
washed with 3 × saturated NaHCO3 and 1 × saturated NaCl,
dried with MgSO4, and then concentrated in vacuo. The
resultant oil was chromatographed (hexane/EtOAc, 4:1) to give
78 as a waxy solid: 95 mg (0.33 mmol, 23%); 1H NMR δ 7.81-
7.75 (m, 4 H), 7.68 (s, 1 H), 7.47-7.36 (m, 3 H), 6.29 (s, 1 H),
5.25 (s, 2 H), 3.27-3.2 (m, 2 H), 3.13-3.08 (m, 2 H); IR 1632,
1572, 1544, 1508 cm-1; MS (EI) m/z 283 (M+). Anal. (C16H14
-
ClN3) C, H, N.
6-Ch lor o-2-[(2-n a p h th a len ylm eth yl)su lfin yl]-4-p yr im -
id in a m in e (79). Compound 5 (30 mg, 0.10 mmol) was
dissolved in MeOH (1 mL) and treated dropwise with a
solution of SeO2 (11 mg, 0.1 mmol) and 30% H2O2 (1 drop) in
MeOH (1 mL). After 1 h, 30% H2O2 (1 drop) was added, and
stirring continued for 30 min. The reaction was diluted with
H2O and filtered. The white precipitate was washed with
acetone and air-dried to give 79: 15 mg (0.047 mmol, 47%);
1
mp 222-223 °C; H NMR (DMSO) δ 7.87 (m, 4 H), 7.73 (s, 2
H), 7.53 (m, 2 H), 7.25 (d, J ) 8.4 Hz, 1 H), 6.50 (s, 1 H), 4.53
(d, J ) 12.8 Hz, 1 H), 4.37 (d, J ) 12.8 Hz, 1 H); IR 1612,
1574, 1518 cm-1; MS (EI) m/z 318 (M+). Anal. (C15H12ClN3-
OS) C, H, N.
6-Ch lor o-2-[[(3-br om op h en yl)m eth yl]su lfin yl]-4-p yr i-
m id in a m in e (80). Compound 34 (0.16 mg, 0.50 mmol) was
dissolved in CH2Cl2 (10 mL) at 0 °C, treated with 50% mCPBA
(0.17 mg, 0.50 mmol), and stirred overnight at room temper-
ature. The solid was collected and washed with MtBE to give
80: 77 mg (0.22 mmol, 44%); mp 216-217 °C (acetonitrile);
1H NMR (DMSO) δ 7.49 (d, J ) 7.5 Hz, 1 H), 7.32 (m, 1 H),
7.27 (t, J ) 7.7 Hz, 1 H), 7. 12 (d, J ) 7.6 Hz, 1 H), 6.48 (s, 1
H), 4.38 (d, J ) 12.8 Hz, 1 H), 4.21 (d, J ) 12.8 Hz, 1 H); IR
1646, 1633, 1576, 1520 cm-1; MS (EI) m/z 345 (M+). Anal.
(C11H9BrClN3OS) C, H, N.
6-Ch lor o-2-[[(3-br om op h en yl)m eth yl]su lfon yl]-4-p yr i-
m id in a m in e (81). Compound 34 (0.66 g, 2.0 mmol) was
dissolved in HOAc (5 mL), treated with 30% H2O2 (1 mL), and
stirred for 72 h at room temperature. The reaction was diluted
with EtOAc, washed 1 × H2O, 3 × saturated NaHCO3, and 1
× saturated NaCl, then dried with MgSO4, and concentrated
in vacuo. The residue was chromatographed (EtOAc/hexane,
1:1), then dissolved in acetone, and knocked out with H2O: 286
The crude mesylate (11.8 g, 45.0 mmol) and KCN (11.7 g,
0.18 mol) in DMF (67 mL) were heated to 60-70 °C for 15 h.
After cooling, the reaction was poured into H2O (500 mL),
which was then extracted with 4 × 75 mL of MtBE. The
combined organic layers were washed with H2O and saturated
NaCl, dried with MgSO4, and concentrated in vacuo to give
the nitrile 76: 5.38 g (29.7 mmol, 66%); mp 76-77 °C (heptane/
1
mg (0.790 mmol, 39%); mp 191-192 °C; H NMR (DMSO) δ
8.19 (s, 1 H), 7.95 (s, 1 H), 7.56 (m, 2 H), 7.33 (m, 2 H), 6.45 (s,
1 H), 4.87 (s, 2 H); IR 1648, 1639, 1576, 1515 cm-1; MS (EI)
m/z 361 (M+). Anal. (C11H9BrClN3O2S) C, H, N.
1
toluene); H NMR δ 7.84-7.79 (m, 3 H), 7.69 (s, 1 H), 7.52-
7.44 (m, 2 H), 7.36-7.33 (m, 1 H), 3.13 (t, J ) 7.4 Hz, 2 H),
2.71 (t, J ) 7.4 Hz, 2 H).
HIV RT Assa y. The standard reaction mixture for the RT
assay contained 2 mM dithiothreitol, 60 mM NaCl, 10 mM
MgCl2, 50 µM Tris-HCl (pH 8.3), 0.05% Nonidet P-40, 50 µM
thymidine triphosphate with 12 µCi/mL [methyl-3H]thymidine
5′-triphosphate (Amersham), 200 nM template:primer (poly-
(rA)600:oligo(dT)10; from Pharmacia), and 4 homodimers and
was obtained as previously described.11,21,22 The assay was
carried out at 28 °C for 10 min in a total volume of 100 µL.
The enzyme reaction was terminated by addition of 100 µL of
trichloroacetic acid (10%, v/v). The acid-precipitated materials,
recovered on glass fiber filters by Micro96 Harvester (SKA-
TRON), were analyzed for radioactivity.
Into a -78 °C solution of 76 (2.04 g, 11.2 mmol) in absolute
EtOH (40 mL) and CH2Cl2 (150 mL) was bubbled HCl for 20
min. When the addition was complete, the reaction was
warmed to -20 °C and maintained for 2 h. The mixture was
concentrated in vacuo to give the crude imido ester HCl: 1.52
g (5.80 mmol, 51%); H NMR δ 7.90-7.86 (m, 4 H), 7.78 (s, 1
H), 7.54-7.44 (m, 3 H), 4.41 (q, J ) 7.0 Hz, 2H), 3.16-3.05
(m, 4 H), 1.29 (t, J ) 7.0 Hz, 3 H).
1
To a solution of NH3/MeOH (3.9 M, 25 mL, 97 mmol) at 0
°C was added the imido ester‚HCl salt (1.27 g, 4.8 mmol) in
several portions. The solution was stirred at 0 °C for 20 min
and then at 22 °C for 1 h. The reaction mixture was
concentrated in vacuo, then resuspended in 1:1 EtOH/CHCl3
(30 mL), cooled, and filtered. The resultant solid was dried
under vacuum to provide 77 as a white powder which was used
without further purification: 1H NMR δ 7.78-7.74 (m, 3 H),
7.67 (s, 1 H), 7.45-7.34 (m, 3 H), 3.14 (t, J ) 7.1 Hz, 2 H),
2.81 (t, 2 H).
Compound 77 (1.08 g, 4.60 mmol) and ethyl cyanoacetate
(0.52 g, 4.6 mmol) in MeOH (5 mL) were treated with a
solution of NaOMe (25% in MeOH, 1.1 mL, 4.8 mmol) and then
heated at reflux for 24 h. After cooling, the mixture was
filtered, and the solids were washed with 2 × cold MeOH and
H2O: 0.43 g (1.6 mmol, 35%). The hydroxypyrimidine (0.379
g, 1.43 mmol) was treated with POCl3 (1.2 mL, 13 mmol) and
2-picoline (0.14 mL, 1.4 mmol) and then heated to reflux for
22 h. After cooling, the reaction was quenched on ice and
heated to reflux for 30 min. The reaction was cooled, adjusted
to pH 10 with concentrated NH4OH, and again heated to reflux
for 1 h. After cooling, the residue was dissolved in EtOAc,
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