Solid phase synthesis of hydroxy benzothiazepinones through cyclative release under thermolysis

Article abstract of DOI:10.1246/cl.2004.888

Hydroxy benzothiazepinones were synthesized by a simple procedure involving epoxidation of polymer bound cinnamic acids followed by nucleophilic opening of the resulting glycidic ester by o-aminothiophenol to afford the intermediate hydroxy anilino-esters which underwent cyclization cleavage on heating in DMF to release the product completely.

Full text of DOI:10.1246/cl.2004.888

888
Chemistry Letters Vol.33, No.7 (2004)
Solid Phase Synthesis of Hydroxy Benzothiazepinones
through Cyclative Release under Thermolysis
H. M. Sampath Kumar,ꢀ P. Pawan Chakravarthy, M. Shesha Rao, Sipak Joyasawal, and J. S. Yadav
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500 007, India
(Received December 1, 2003; CL-031167)
Hydroxy benzothiazepinones were synthesized by a simple
the epoxidation of less reactive internal olefins.6 The resin bound
procedure involving epoxidation of polymer bound cinnamic
acids followed by nucleophilic opening of the resulting glycidic
ester by o-aminothiophenol to afford the intermediate hydroxy
anilino-esters which underwent cyclization cleavage on heating
in DMF to release the product completely.
glycidic ester was treated with o-aminothiophenol at 80 ꢁC in dry
toluene in the presence of a catalytic amount of DIPEA to give
the desired amino alcohol. IR (on resin) and 1H NMR spectra of
the residue obtained after cleavage of compound 4 confirmed the
formation of glycidic esters and the successive opening. Epoxy
ring opening was regioselective as found in solution phase syn-
thesis. Furthermore, by varying the substitution on the aromatic
ring of the o-aminothiophenol, molecular diversity on the benzo-
thiazepinone nucleus can be achieved at this point. It is pertinent
to mention here that the 8-chloro derivative known as Clentia-
zem is also a powerful calcium channel blocker, which was also
developed by the discoverers of Diltiazem. The cyclization was
effected merely by heating the resin bound compound in DMF at
140–150 ꢁC under nitrogen, which completely released the prod-
uct. We were able to synthesize a number of benzothiazepinone
derivatives employing the above strategy7 and the purity of the
final products could be determined by GC analysis of the residue
obtained after cyclative cleavage. As Diltiazem and the other de-
rivatives belonging to this family are marketed in optically pure
form which could be achieved either through resolution of the
mercapto-acid intermediate as a chiral amine salt or through di-
Benzothiazepinones are excellent pharmacophores and
some of the hydroxy derivatives are marketed as life saving car-
diovascular drugs which are utilized for the treatment of supra
ventricular arrhythmia e.g., Diltiazem—developed and marketed
by a Japanese company—Tanabe Seiyaku1 is one of the top
twenty products2 in global pharmaceutical market sales in the
past two decades, which clearly reflects the significance of ben-
zothiazepinones as therapeutic entities.
OMe
S
O
CH3
N
O
P
O
Cl
O
O
ONa
O
P
DMF,
Ar
Ar
N
2
1
H3C
CH3
Figure 1. Diltiazem.
SH
Solid phase synthesis has emerged as an important paradigm
for the high throughput screening in modern drug discovery.3 Of
particular interest would be the thermal or base promoted cycla-
tive release technique adopted for the combinatorial synthesis of
a variety of therapeutic molecules including benzodiazepi-
nones.4 Even though a number of solution phase strategies were
employed for the synthesis of benzothiazepinones, this has not
yet been a target for solid phase synthesis. Our continued efforts
towards the development of new solid phase methodologies5 and
their applications to the synthesis of small molecular libraries,
prompted us to explore the solid phase synthesis of benzothiaze-
pinones employing a cyclative release strategy.
O
toluene, m-CPBA
DIPEA
NH2
O
O
P
toluene,
Ar
3
HO
O
OH
Ar
Ar
O
P
O
DMF,
Cyclative Release
S
NH2
S
NH
Resin bound (E)-cinnamic acids were prepared through con-
densation of the sodium salts of various substituted trans-cin-
namic acids with the Merrifield resin in DMF at 70–80 ꢁC.
The initial loading level was determined by gain of weight after
the first condensation and also by cleaving a known quantity of
the loaded resin by treatment with TFMSA and analyzing the
residue quantitatively. The resin bound cinnamic acids were sub-
jected to epoxidation by treatment with m-CPBA at 90 ꢁC. The
procedure followed was in analogy with literature methods for
5
4
MeO
MeO
O2N
MeO
Cl
Ar =
,
,
,
,
MeO
P
= Merrifield resin
Scheme 1.
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.7 (2004)
889
Table 1. Solid phase synthesis of hydroxybenzothiazepinones
(1999); F. Balkenhohl, C. Bussche-Hunnegeld, A. Lansky,
and C. Zechel, Angew. Chem., Int. Ed. Engl., 35, 2288
(1996).
a,b
Product(5)
Entry
a
Yield (Purity)/%
Ar
4
J. P. Mayer, J. Zang, K. Biergarde, D. M. Lenz, and J. J.
Gaudino, Tetrahedron Lett., 37, 8081 (1996); A. L. Smith,
C. G. Thompson, and P. D. Leeson, Bioorg. Med. Chem.
Lett., 6, 1483 (1996); S. A. Kolodziej and B. C. Hamper,
Tetrahedron Lett., 37, 5277 (1996); B. A. Dressman, L. A.
Spangle, and S. W. Kaldor, Tetrahedron Lett., 37, 937
(1996); L. Gouilleux, J. A. Fehrentz, F. Wintsernitz, and
J. Martinez, Tetrahedron Lett., 37, 7031 (1996).
H. M. S. Kumar, S. Anjaneyulu, B. V. S. Reddy, and J. S.
Yadav, Synlett, 2000, 1129; H. M. S. Kumar, P. P.
Chakravarthy, M. Shesha Rao, and P. S. R. Reddy, Tetrahe-
dron Lett., 43, 7817 (2002).
OH
70(72)
O
S
NH
OH
O
MeO
b
MeO
76(78)
S
NH
5
6
7
OH
O
c
Cl
Cl
V. R. Valente and J. L. Wolfhagen, J. Org. Chem., 31, 2509
(1966); Y. Kishi, M. Aratani, H. Tanino, T. Fukuyama, T.
Goto, S. Inoue, S. Sugiura, and H. Kakoi, J. Chem. Soc.,
Chem. Commun., 1972, 65.
S
75(73)
72(77)
NH
O2N
O2N
OH
The sodium salt of (E)-4-methoxycinnamic acid 1, (1 g,
8.0 mmol) was heated with Merrifield Resin (0.1 g,
0.8 mmol/g, Advanced ChemTech, USA, 100–200 mesh)
in DMF at 70–80 ꢁC for 24 h at the end of which the resin
was filtered and washed with DMF, DCM, and MeOH alter-
natively and dried under vacuum to afford the resin bound
cinnamic acid ester 2: FTIR (KBr): 1733 cmꢂ1. Weight gain
after condensation and also GC analysis of the residue ob-
tained after cleavage revealed almost quantitative loading
(0.8 mmol/g). The resultant resin 2 was treated with m-
CPBA (300 mg, 1.7 mmol) in toluene and heated (90 ꢁC)
for 4 days under nitrogen. The resin was filtered, washed
(DMF, DCM, and MeOH) and dried under vacuum to get
O
d
e
S
NH
MeO
MeO
MeO
OH
O
80(75)
MeO
MeO
S
NH
MeO
a. Overall yield calculated based on initial loading level.
b. Purity based on the GC analysis of the crude product (after
release).
polymer bound glycidic ester 3: FTIR (KBr): 1728 cmꢂ1
.
astereoselective synthesis via asymmetric epoxidation using chi-
ral dioxiranes.8 Currently, efforts are underway to prepare the
optically active hydroxy glycidic esters on solid phase.
In conclusion, we present in this paper a solid phase synthe-
sis of hydroxy benzothiazepinones employing a cyclative release
technique. The strategy can be conveniently adapted to various
commercially available o-aminothiophenols and is found to be
general with regard to various substituted cinnamic acids to af-
ford an array of substituted hydroxy benzothiazepinones of bio-
logical importance.
Resin bound compound 3 (R1 = MeO–C6H4) was heated
with o-aminothiophenol (0.33 g, 3.0 mmol) and catalytic
quantity of DIPEA (0.1 mmol) in toluene (80 ꢁC) for 12 h un-
der nitrogen followed by filtration, washing with DCM and
MeOH and drying to afford anilino ester 4: FTIR (KBr):
1725 cmꢂ1. Resin bound anilino ester 4 on heating in DMF
at 140–150 ꢁC for 12 h under nitrogen released the product
5 completely into the solution. The resin was removed by fil-
tration and the filtrate was evaporated under reduced pres-
sure (residue, GC, 78%), followed by purification by prepa-
rative thin layer chromatography to afford 18.3 mg of
benzothiazepinone 5b as amorphous white solid. Yield
The authors are thankful to IFCPAR 2305-1 for financial as-
sistance and thank Dr. I. A. Ansari for helpful discussions.
(overall): 76%, IR (KBr): 1704 cmꢂ1 1H NMR (DMSO-
;
d6) ꢀ: 3.21–3.25 (br d, 1H, OH), 3.80 (s, 3H, OCH3),
4.33–4.40 (t, 1H, J ¼ 7:0, CHOH), 5.0–5.04 (d, 1H, J ¼
7:0 Hz, S-CH) and aromatic protons at 6.82–6.86 (d, 2H,
J ¼ 8:8 Hz), 7.1–7.2 (m, 2H), 7.3–7.32 (d, 1H, J ¼ 1:6),
7.40–7.44 (d, 2H, J ¼ 8:8 Hz), 7.57–7.60 (d, 1H, J ¼
References and Notes
1
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52, Suppl. l, 147 (1983); A. Abe, H. Inoue, and T. Nagao,
Yakugaku Zasshi, 108, 716 (1988).
7:6 Hz)
& 10.2 (br, s, 1H, NH). EIMS m=z: 283
(Mþ ꢂ H2O, 100%), 301 (Mþ, 31%).
8
M. Seki, T. Furutani, R. Imashiro, T. Kuroda, T. Yamanaka,
N. Harada, H. Arakawa, M. Kusama, and T. Hashiyama,
Tetrahedron Lett., 42, 8201 (2001).
2
3
S. H. DeWitt and A. W. Czarnik, Acc. Chem. Res., 29, 114
(1996); SCRIP, No. 2040, July 7 (1995), p 23.
B. A. Lorsbach and M. J. Kurth, Chem. Rev., 99, 1549
Published on the web (Advance View) June 21, 2004; DOI 10.1246/cl.2004.888