A facile synthesis of novel 2-amino-6-arylmethyl-7-carboxamido-7,8- dihydropyrimido[5,4-f][1,4]thiazepin-5-ones

Article abstract of DOI:10.1016/j.tetlet.2010.06.070

A facile synthesis of novel 2-amino-6-arylmethyl-7-carboxamido-7,8- dihydropyrimido[5,4-f][1,4]thiazepin-5-ones is described. The synthesis was developed on solid phase and was applied to provide a series of analogs in good yield. The key reactions are acylation of a cysteine derivative with 2,4-dichloropyrimidine-5-carbonyl chloride followed by cyclization to generate a 6-arylmethyl-7-carboxamido-2-chloro-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5- one, which is further derivatized with an amine to give the desired 2-amino-6-arylmethyl-7-carboxamido-7,8-dihydropyrimido[5,4-f][1,4] thiazepin-5-one.

Full text of DOI:10.1016/j.tetlet.2010.06.070

Tetrahedron Letters 51 (2010) 4486–4489
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Tetrahedron Letters
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A facile synthesis of novel 2-amino-6-arylmethyl-7-carboxamido-7,8-dihydro-
pyrimido[5,4-f][1,4]thiazepin-5-ones
a
a
a
a
a
Lan-Ying Qin a, , Andrew G. Cole , Axel Metzger , Marc-Raleigh Brescia , Kurt W. Saionz , Joan J. Zhang ,
Pascal Rigollier b, James R. Wareing c, Hubert Gstach d, Juerg Zimmermann b, Roland E. Dolle a,
John J. Baldwin a, Ian Henderson a
*
a Ligand Pharmaceuticals Inc., 3000 Eastpark Blvd., Cranbury, NJ 08512, USA
b Novartis Institutes for Biomedical Research, Basel, Switzerland
c Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA
d Novartis Institutes for Biomedical Research, Vienna, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile synthesis of novel 2-amino-6-arylmethyl-7-carboxamido-7,8-dihydropyrimido[5,4-f][1,4]thiaze-
pin-5-ones is described. The synthesis was developed on solid phase and was applied to provide a series
of analogs in good yield. The key reactions are acylation of a cysteine derivative with 2,4-dichloropyrim-
idine-5-carbonyl chloride followed by cyclization to generate a 6-arylmethyl-7-carboxamido-2-chloro-
7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-one, which is further derivatized with an amine to give the
desired 2-amino-6-arylmethyl-7-carboxamido-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-one.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 1 April 2010
Revised 7 June 2010
Accepted 14 June 2010
Available online 18 June 2010
Keywords:
Dihydropyrimidothiazepinone
Solid phase
Molecules incorporating
a
dihydrobenzothiazepinone motif
consuming. Solid-phase chemistry can simplify the process, allow-
ing the removal of excess reagents and solution impurities by
washing the solid-phase resin with solvents.11 As such, solid-phase
chemistry when applicable can greatly facilitate a synthetic strat-
egy. The synthesis of novel 2-amino-6-arylmethyl-7-carboxa-
mido-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-ones described
here was developed on solid phase.
(Fig. 1, X, Y = CH) exhibit a wide and diverse range of biological
activity. Dihydrobenzothiazepinones have been reported that are
antipsychotics,1 antidepressants,2 suppressors of proliferation of
the HIV virus,3 and cysteine protease inhibitors.4 They have also
been reported to prevent cardiac arrhythmia, heart failure, and
atrial fibrillation by targeting RyR receptors.5 Syntheses of
dihydrobenzothiozepinones have been extensively reported. The
common methods involve reacting 2-mercaptobenzoic acids with
2-amino alcohol esters,6 ethylenimine,6 nitroethene,7 b-haloam-
ines,8 or via a Schmidt rearrangement of 1-thio-4-chromanones.9
Pyrimido-[1,4]-thiazepinones (Fig. 1, X, Y = N) are closely related
and isosteric to dihydrobenzothiazepinones, and thus will likely
also possess interesting biological activity. It is therefore some-
what surprising that no work has been reported on synthetic strat-
egies directed toward this class of molecules. Only one report by
Safonova and co-workers detailing the synthesis of the isomeric
pyrimido-[1,5]-thiazepinones can be found in the literature.10
The synthesis described below provides a facile method to gener-
ate novel 2-amino-6-arylmethyl-7-carboxamido-7,8-dihydropy-
rimido[5,4-f][1,4]thiazepin-5-ones.
Solid-phase synthesis was initiated by acylating aminomethyl-
terminated TentaGelÒ resin
1 with N-a-N-e-bis-Fmoc-lysine
followed by Fmoc deprotection to generate 2 (Scheme 1). This
increases the loading capacity of the resin by doubling the number
of amino groups for further derivatization. The double-loaded resin
2 was subsequently acylated with the photo-labile linker precursor
4-carboxy-2-nitrobenzyl bromide to give 3. This linker allows
cleavage of intermediates and product from solid phase by irradi-
ation with light at 330 nm, and is compatible with the chemistry
utilized in this synthetic strategy.12 Reaction of benzyl bromide 3
with a primary amine provided the resin-bound secondary amine
4. A large excess of amine was utilized in order to minimize unde-
sired cross-linking between unreacted benzyl bromide and the
secondary amine formed during this reaction. A range of primary
amines (R1NH2) were successfully utilized in this reaction se-
quence (Table 1).
In a typical multi-step solution-phase synthesis, reaction work
up and intermediate purification are often labor intensive and time
The secondary amine
4 was subsequently acylated with
N-Fmoc-S-Trt-cysteine, followed by Fmoc deprotection to give 5
(Scheme 2). Both enantiomers of N-Fmoc-S-Trt-cysteine were suc-
cessfully utilized. The resin-bound primary amine 5 was further
* Corresponding author. Tel.: +1 609 720 0599; fax: +1 609 655 4187.
E-mail address: lanying_qin@yahoo.com (L.-Y. Qin).
In 2008, Pharmacopeia, Inc. was acquired by Ligand Pharmaceuticals, Inc.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.070

L.-Y. Qin et al. / Tetrahedron Letters 51 (2010) 4486–4489
4487
R
O
N
R'
X
S
Y
R"
Figure 1. Dihydrobenzo-[1,4]-thiazepinone (X, Y = CH) and dihydropyrimido-[1,4]-thiazepinone (X, Y = N) motifs.
O
Br
NO2
O
H
N
N
4 NH2
N
H
NH2
c
a,b
H
O
4
NH2
HN
2
3
1
O
NO2
Br
R1
O
N
H
H
N
N
NO2
L
NH
R1
d
H
=
O
4
HN
4
4
O
NO2
NH
R1
Scheme 1. Reagents and conditions: (a) N-
a-N-
e-bis-Fmoc-Lys, HOBt monohydrate, DIC, CH2Cl2, DMF, 25 °C, 16 h; (b) piperidine, DMF, 25 °C, 1 h; (c) 4-carboxy-2-
nitrobenzyl bromide, HOBt monohydrate, DIC, CH2Cl2, DMF, 25 °C, 16 h; (d) R1-NH2, THF, 25 °C, 16 h.
Table 1
2-Amino-6-arylmethyl-7-carboxamido-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-ones
R2
O
O
R1
N
N
H
N
S
N
R3
11
Compound
R1
Configuration
R2
R3
pmol per beada
637
Yieldb (%)
49
Purityc (%)
87
F
N
H
O
11a
R
O
F
N
11b
11c
11d
S
525
538
347
40
41
27
93
91
79
N
H
O
N
R
R
O
O
O
N
O
N
H
Cl
N
11e
11f
R
S
226
285
17
22
84
62
N
O
N
H
O
Cl
N
H
Cl
11g
R
497
38
78
Cl
a
b
c
Based on comparison with an analytical reference.
Based on average loading per bead.
Based on HPLC analysis at 215 nm.

4488
L.-Y. Qin et al. / Tetrahedron Letters 51 (2010) 4486–4489
R2
R2 Cl
N
N
Cl
O
O
O
NH
N
f
e
NH2
STrt
c,d
a,b
L
NH
R1
L
N
L
N
R1
N
R1
L
R1
O
STrt
STrt
4
6
7
5
R2
R2
R2 Cl
N
N
Cl
R2
O
O
O
O
O
O
O
g
N
S
N
S
i
N
h
N
S
N
R1
L
L
L
N
R1
N
R1
HN
R1
O
N
N
N
SH
N
N
N
R3
R3
Cl
8
11
9
10
Scheme 2. Reagents and conditions: (a) N-Fmoc-S-Trt-cysteine, HOBt monohydrate, DIC, CH2Cl2, DMF, 25 °C, 16 h; (b) piperidine, DMF, 25 °C, 1 h; (c) R2CHO, THF, 25 °C, 16 h;
(d) NaCNBH3, MeOH, AcOH, 25 °C, 16 h; (e) 2,4-dichloropyrimidine-5-carbonyl chloride, DIEA, CH2Cl2, 25 °C, 3 h; (f) TFA, Et3SiH, CH2Cl2, 25 °C, 0.5 h; (g) DIEA, CH2Cl2, 25 °C,
3 h; (h) amine R3H, THF, 25 °C, 16 h; (i) isopropanol/H2O/TFA (80:20:3), h
m (330 nm), 50 °C, 1 h.
Figure 2. (A) HPLC profile of the standard of 11a at 215 nm. (B) HPLC profile of the crude bead eluent of 11a at 215 nm.
derivatized through reductive alkylation with an aldehyde to give
amine at room temperature. This cyclization of the thiol group
with the 2,4-dichloropyrimidine moiety proceeded smoothly and
in good yield. Subsequent reaction of 9 with an amine gave the re-
sin-bound 2-amino-6-arylmethyl-7-carboxamido-7,8-dihydropy-
rimido[5,4-f][1,4]thiazepin-5-one 10. A range of primary and
secondary amines incorporating the R3 substitution were success-
fully used in this reaction (Table 1). Cleavage of 10 from solid phase
via photolysis gave the desired 2-amino-6-arylmethyl-7-carboxa-
mido-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-one 11.
To determine the yields and purities of 11a–g following the
photolysis, the combined eluent from 20 beads of each compound
was quantitatively analyzed versus an analytically pure sample of
the corresponding 2-amino-6-arylmethyl-7-carboxamido-7,8-
dihydropyrimido[5,4-f][1,4]thiazepin-5-one.14 Released compound
6. To ensure mono-alkylation of the primary amine, a two-step
reductive alkylation was performed. This involved imine forma-
tion, removal of excess aldehyde, and subsequent imine reduction
with sodium cyanoborohydride. A number of aromatic aldehydes
(R2CHO) that incorporate both electron-rich and electron-deficient
substituents were used (Table 1).
The resin-bound secondary amine 6 was subsequently acylated
with 2,4-dichloropyrimidine-5-carbonyl chloride13 to give 7. No
by-product resulting from N-arylation with the chloropyrimidine
was observed. Acid-catalyzed removal of the trityl group gave thiol
8. The key cyclization reaction to give 6-arylmethyl-7-carboxa-
mido-2-chloro-7,8-dihydropyrimido[5,4-f][1,4]thiazepin-5-one
9
was then achieved by treatment of 8 with N,N-diisopropylethyl-

L.-Y. Qin et al. / Tetrahedron Letters 51 (2010) 4486–4489
6. Wuensch, K. H.; Ehlers, A.; Beyer, H. Chem. Ber. 1969, 102, 1618–1625.
4489
yields ranged from 17% to 49% over 10 steps (Table 1). The purity
levels of crude 2-amino-6-arylmethyl-7-carboxamido-7,8-dihyd-
ropyrimido[5,4-f][1,4]thiazepin-5-one 11a–g were high, which is
exemplified by the HPLC chromatogram for crude 11a in Figure 2.
In conclusion, a facile solid-phase synthesis of novel 2-amino-6-
arylmethyl-7-carboxamido-7,8-dihydropyrimido[5,4-f][1,4]thiaze-
pin-5-ones 11 has been developed. The synthesis performed well
with a wide range of R1, R2, and R3 components. This synthetic
strategy can be readily applied to the construction of both parallel
7. Czollner, L.; Szilagyi, G.; Lango, J. G. Magy. Kemiai Folyoirat 1988, 94,
332–335.
8. Wuensch, K. H.; Ehlers, A.; Beyer, H. Zeitschrift Chem. 1967, 7, 185–186.
9. Wuensch, K. H.; Stahnke, K. H.; Ehlers, A. Chem. Ber. 1970, 103, 2302–2307.
10. Keremov, A. F.; Nemeryuk, M. P.; Aparnikova, O. L.; Safonova, T. S. Khimiya
Geterotsiklicheskikh Soedinenii 1977, 10, 1332–1335.
11. (a) Dolle, R. E. J. Comb. Chem. 2000, 2, 383–433; (b) Dolle, R. E.; Le Bourdonnec,
B.; Goodman, A. J.; Morales, G. A.; Thomas, C. J.; Zhang, W. J. Comb. Chem. 2009,
11, 739–790.
12. (a) Rich, D. A.; Gurwara, S. K. J. Am. Chem. Soc. 1975, 97, 1575–1579; (b) Barany,
G.; Albericio, F. J. Am. Chem. Soc. 1985, 107, 4936–4942.
and
combinatorial
2-amino-6-arylmethyl-7-carboxamido-7,
13. To a stirred solution of 10 g (64 mmol, 1.0 equiv) of 2,4-dihydroxypyrimidine-
5-carboxylic acid in 50 mL of phosphorus oxychloride was added 34 mL
(190 mmol, 3.0 equiv) of diisopropylethylamine over approximately 2 h. The
reaction mixture was heated at reflux for 16 h, allowed to cool to ambient
temperature, and the volatiles removed by distillation. The remaining residue
was extracted twice with diethyl ether (2 Â 200 mL). The volatiles were
removed in vacuo and the residue was purified by Kugelrohr distillation to
obtain 8.7 g (41 mmol, 64%) of 2,4-dichloropyrimidine-5-carbonyl chloride as a
yellow oil.
8-dihydropyrimido[5,4-f][1,4]thiazepin-5-one libraries, which
should allow the rapid and useful exploitation of this chemotype.
References and notes
1. (a) Kurz, T.; Geffken, D.; Mesaros, R. WO2005082873.; (b) Tanaka, K.; Kurotia,
T.; Ishibuchi, S.; Ushio, H.; Futamura, T.; Ohashi, Y.; Yano, K. WO9703986.
2. Krapcho, J.; Turk, C. F.; Piala, J. J. J. Med. Chem. 1968, 11, 361–364.
3. Nakamura, T.; Watanabe, W.; Ikeda, A. JP2003119137.
4. Ohmoto, K.; Itagaki, I. WO2001055118.
5. Marks, A. R.; Landry, W.; Deng, S. X.; Zhen, Z. US2005187386.
14. Analytical standards of 11a–g were synthesized on solid phase via the
described synthetic route and subsequently purified by semi-preparative
HPLC. Analytical HPLC analysis was conducted using a PDA-linked Waters
Millenium 2690 and Phenomenex Luna 3
lm 50 Â 3 mm C8 column.