Synthesis of N-carboxyalkyl-1,4-benzothiazepine-3(2H)-one derivatives using esters of N-(2-chloro-5-nitrobenzyl)amino acids

Article abstract of DOI:10.1007/s00706-013-1133-1

Two alternative approaches for synthesis of esters of N-(2-chloro-5- nitrobenzyl) amino acids have been developed and compared. We have found synthesis of N-(2-chloro-5-nitrobenzyl) amino acids via alkylation of esters of amino acids in DMF in the presence of Et₃N and NaI to be more convenient and have higher yields in comparison with reduction of Schiff bases obtained from 2-chloro-5-nitrobenzaldehyde and corresponding esters of amino acids by NaBH₄. Treatment of the solutions of esters of N-(2-chloro-5-nitrobenzyl) amino acids in DMSO with methyl thioglycolate and following intramolecular acylation in xylene led to N-carboxyalkyl-1,4- benzothiazepine-3(2H)-one derivatives in 24-76 % yields. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-013-1133-1

Monatsh Chem
DOI 10.1007/s00706-013-1133-1
ORIGINAL PAPER
Synthesis of N-carboxyalkyl-1,4-benzothiazepine-3(2H)-one
derivatives using esters of N-(2-chloro-5-nitrobenzyl)amino acids
•
Taras M. Tarasiuk Tetiana A. Volovnenko
•
•
•
Yulian M. Volovenko Volodymyr V. Medviediev
Oleg V. Shishkin
Received: 27 June 2013 / Accepted: 11 December 2013
Ó Springer-Verlag Wien 2014
Abstract Two alternative approaches for synthesis of
esters of N-(2-chloro-5-nitrobenzyl) amino acids have been
developed and compared. We have found synthesis of N-
(2-chloro-5-nitrobenzyl) amino acids via alkylation of
esters of amino acids in DMF in the presence of Et3N and
NaI to be more convenient and have higher yields in
comparison with reduction of Schiff bases obtained from
2-chloro-5-nitrobenzaldehyde and corresponding esters of
amino acids by NaBH4. Treatment of the solutions of esters
of N-(2-chloro-5-nitrobenzyl) amino acids in DMSO with
methyl thioglycolate and following intramolecular acyla-
tion in xylene led to N-carboxyalkyl-1,4-benzothiazepine-
3(2H)-one derivatives in 24–76 % yields.
approaches for the synthesis of possible isomers, their
biological activity and the usage in medicine. The ben-
zothiazepine cycle is known to have ten isomers which can
be divided into three groups: derivatives of 1,2-, 1,3-, and
1,4-thiazepines (Fig. 1) [1].
Our research group is interested in derivatives of 1,4-
thiazepine III that include three isomers with an annulated
phenyl ring: 1,4-, 4,1-, and 5,1-benzothiazepines. The 1,5-
benzothiazepines [2–4] are more studied than 1,4- and 4,1-
isomers [5–8].
Earlier, we have reported two alternative methods of
synthesis of 1,4-benzothiazepine-3(2H)-ones [9, 10]. The
objective of the present work was synthesis of novel 1,4-
benzothiazepine-3(2H)-one derivatives, which contain
fragments of amino acids in position 4. To our mind, the
combination of a rigid nonplanar cycle and an amino
acid residue can lead to the appearance of useful bio-
logical properties. There are a lot of pharmaceuticals
based on peptides or containing amino acids in medicine.
Saturated and partially saturated rigid seven-membered
heterocycles are known to be a base of drugs. For
example, CV5975 (IV) [11] is a synthetic inhibitor of
angiotensin-converting enzyme (ACE), which plays an
important role in regulating arterial blood pressure
(Fig. 2).
Keywords Amino acids ꢀ Heterocycles ꢀ Cyclizations ꢀ
Nucleophilic substitutions ꢀ X-ray structure determination ꢀ
1,4-Benzothiazepine-3(2H)-ones
Introduction
For the last decades, benzothiazepines have received
noticeable attention from organic chemists due to various
Compounds of general formula V [12] were found to be
potent agonists of bradykinin B2 receptors. Bradykinin
(BK) is a linear nonapeptide hormone (HArg-Pro-Pro-Gly-
Phe-Ser-Pro-Phe-Arg-OH), which is involved in a wide
variety of physiological and pathophysiological responses
through activation of two types of receptors named B1 and
B2. Bradykinin induces vascular and bronchial smooth
muscle contraction and causes vasodilation and microvas-
cular leakage [3].
T. M. Tarasiuk (&) ꢀ T. A. Volovnenko ꢀ Y. M. Volovenko
Department of Organic Chemistry, Taras Shevchenko Kyiv
National University, 64 Volodymyrska str., 01033 Kyiv, Ukraine
e-mail: taras88ximik@ukr.net
V. V. Medviediev ꢀ O. V. Shishkin
STC ‘‘Institute for Single Crystals’’, National Academy of
Science of Ukraine, 60 Lenina ave., 61001 Kharkiv, Ukraine
O. V. Shishkin
Department of Inorganic Chemistry, V. N. Karazin Kharkiv
National University, 4 Svobody sq., 61122 Kharkiv, Ukraine
123

T. M. Tarasiuk et al.
Method A is restricted because of side reactions and
only some esters of N-(2-chloro-5-nitrobenzyl)amino acids
(4b, 4c, 4f) can be obtained through following this tech-
nique. Method B is based on reduction of 2-chloro-5-
nitrobenzaldehyde (1) by NaBH4 in methanol with the
following substitution of a hydroxyl group with chlorine
with SOCl2 similar to a described technique [14]. Treat-
ment of solutions of esters 2a–2f in DMF with 2-chloro-5-
nitrobenzyl chloride (6) in the presence of Et3N and KI
(Scheme 2) afforded compounds 4a–4f in 58–86 % yields
(Table 1). The NMR spectra and other characteristics of
obtained compounds 4b, 4c, 4f using both methods are
identical. According to experimental data shown in
Table 1, method B is more convenient and allows obtain-
ing N-(2-chloro-5-nitrobenzyl) amino acid derivatives 4a–
4f. At the same time, method A can be used only for 4b, 4c,
4f.
-
1 5
,
N
S
N
S
-
N
S
-
-
2 1
,
1 2
,
-
3 1
,
1 3
,
-
2 3
-
-
,
-
-
4 1
,
3 2
,
1 4
,
2 4
,
I
II
III
Fig. 1 Ten possible isomers of the benzothiazepine cycle
NH
S
N
S
N
NHR
NH
(
)
4
H
C
2
O
O
O
H
C
CO2
H
CO2
Arg OH
-
V 5975
IV
V
Fig. 2 Examples of biologically active compounds, which contain an
amino acid fragment and a benzothiazepine moiety
Next step of the present work was aromatic nucleophilic
substitution of chlorine with a residue of methyl thiogly-
colate and subsequent intramolecular acylation. The first
reaction was carried out in DMSO using Et3N as the base
(Scheme 3). Products 7a–7f were not isolated as individual
compounds. These substances were immediately involved
in cyclization in o-xylene.
Results and discussion
We have examined two alternative routes for synthesis of
esters of N-(2-chloro-5-nitrobenzyl) amino acids 4a–4f
using esters of amino acids 2a–2f and 2-chloro-5-nitro-
benzaldehyde (1) as a source of the 2-chloro-5-nitrobenzyl
moiety.
Table 1 Comparison of two alternative methods of synthesis of
esters of N-(2-chloro-5-nitrobenzyl)amino acids 4a–4f
Initially, we have attempted to synthesize the desired
amino acid derivatives 4a–4f from aldehyde 1 and corre-
sponding hydrochlorides of esters of amino acids 2a–2f
following a modified described technique [13] (method A).
This method is based on the formation of Schiff base 3b,
3c, 3f in CH2Cl2 in the presence of Et3N and MgSO4 and
subsequent reduction by NaBH4 in methanol (Scheme 1) in
48–58 % yields (Table 1). The structure of imines 3b, 3c,
3f is confirmed by the presence of a characteristic singlet of
Entry
AA residue
Yield/%
Method A
Method B
4a
4b
4c
4d
4e
4f
Glycine
Side products
86
80
76
79
69
58
b-Alanine
GABA
78
74
Alanine
Side products
No data
48
1
methyne group in H NMR spectra at 8.45–8.73 ppm and
an intensive band of C=N at 1,634–1,644 cm-1 in IR
Leucine
Phenylalanine
spectra.
Scheme 1
R'
N
H
C O
O2
r
t
,
Et N 10 h
,
3
R
CO2
2)n
H l
C
H2N
+
(
C
H
l M
2C 2 SO
,
g
H
C
4
l
C
c
,
2b 2 2f
1
,
R'
R'
R
CO2
R
CO2
2)n
N
O2
.
aBH Me H rt h O N
1 N
5
, ,
O
,
2
4
N
N
( H )n
C
(
C
H
2
H
. - r
2 i P H H l
O
C
,
-
58 91
l
%
H l
C
l
C
C
-
48 78
%
c
c
,
3b 3 3f
4b 4 4f
,
,
,
:
:
:
=
=
=
e
=
=
=
n =
n =
b
R
R
R
M
R'
R'
R'
H
H
C
1
2
,
,
,
,
,
c
e
M
M
e
n =
Ph
,
f
H
0
2
123

Synthesis of N-carboxyalkyl-1,4-benzothiazepine-3(2H)-one derivatives
Scheme 2
N
H
C O
N
O2
O2
a
e
H
O
N BH M
H
O
,
4
r
t
3 h
,
l
l
l
C
C
94
%
1
5
H
l
2C 2
24 h
C
l
SOC 2
r
t
R'
R
CO2
H l
C
H2N
N
O2
(
2)n
2
H
C
l
C
a
-
4f
4
Et N KI DMF
,
,
3
-
58 86
%
C
80 oC 15 h
95
%
6
,
a: R = Me, R' = H, n = 0
b: R = Me, R' = H, n = 1
c: R = Me, R' = H, n = 2
d: R = Me, R' = Me, n = 0
e: R = Et, R' = CH2CH(CH3)2, n = 0
f: R = Me, R' = CH2Ph, n = 0
Scheme 3
R'
R'
R
CO2
2)n
R
CO2
N
O2
(
C
H
H
M
N
S
CO2
e
N
O2
N
(
C
)
H
o-Xylene
n
a-
2
4
4f
H
O
DM
SO
60 °C 5 h
Et N
,
3
Reflux, 3 h
e
M
CO2
S
,
S
a-
7
7
f
8a, 8b, 8d, 8e or 9a-9c, 9e, 9f
a:
=
=
=
=
n =
e n =
,
:
=
=
=
n =
H
,
8
R
M
M
R'
R'
H
M
8b R
M R'
e
,
1
H
e
0
,
,
,
;
;
-
-
24 76
%
50 68
%
:
e
:
=
(
)
n =
8d R
8e R Et R'
H
H
0
;
C
2C
C
0
=
,
,
3 2
a:
e:
=
=
=
=
n =
:
=
=
:
n =
:
=
n =
H 2
, ;
c
=
9
9
R
R
H R'
,
H R'
,
H
C
9b R H R'
H
1 9
;
R
C
H R'
,
0
,
H
;
C
,
0
,
n =
=
n =
H Ph
0
,
H( H )
9f R H R'
2C
,
;
,
3 2
2
We observed partial hydrolysis of ester groups of amino
acid residues in 4a, 4b, 4e and full hydrolysis in the case of
4c and 4f. However, hydrolysis of compound 8d has not
been noticed. Esters 8 and acids 9 can be easily separated
due to their different solubility in aqueous solution of
NaHCO3. Yields of esters 8 and acid 9 are shown in
Table 2.
The characteristic signals in 1H NMR spectra com-
pounds 8a, 8b, and 9a–9c are singlets of methylene groups
in positions 2 and 5 of the benzothiazepine moiety at
Compounds 8d, 8e and 9e, 9f have spectra different from
the spectra of 8a, 8b, and 9a–9c. The presence of an
asymmetric center in the side chain at nitrogen led to
magnetic nonequivalence of protons of the CH2 groups at
positions 2 and 5. Methylene group 2-CH2 appears as two
doublets at 3.54–4.02 and 4.16–4.71 ppm. Two character-
istic doublets of 5-CH2 group are at 4.58–4.77 and
4.87–5.14 ppm. Carbonyl of the amide group in com-
pounds 8 and 9 appears as an intensive band at
1,619–1,660 cm-1 in IR spectra. Structure of compounds
8a and 8b was confirmed by X-ray diffraction studies
(Figs. 3, 4). A seven-membered ring in both molecules
adopts a boat conformation with deviation of the N1 and
C8 atoms from the mean plane of the remaining atoms of
4.05–4.13
and
4.81–4.85 ppm,
correspondingly.
Table 2 Compounds 8 and 9
Entry R0
n
AA residue Yield/%
˚
˚
the ring by -1.18, -1.16 A for 8a, and 1.15, 1.15 A for
8b, respectively.
Ester 8a
Acid 9 (R = H)
In summary, we have synthesized a number of
novel 1,4-benzothiazepine derivatives with alkylcarboxy
substituents (acids and esters) in position 4 of the cycle
in 24–76 % yields. We have developed a convenient
and efficient method for synthesis of esters of
N-(2-chloro-5-nitrobenzyl) amino acids via alkylation of
esters of corresponding amino acids by 2-chloro-5-
nitrobenzylchloride.
a
b
c
d
e
f
H
0
1
2
0
0
0
Gly
68
65
25
24
H
b-Ala
GABA
Ala
H
Not obtained 76
Me
60
50
Not obtained
40
CH2-i-Pr
CH2Ph
Leu
Phe
Not obtained 57
a
Compounds 8a, 8b, 8d are methyl esters, 8e is ethyl ester
123

T. M. Tarasiuk et al.
Preparation of Schiff bases 3b, 3c, 3f
To a stirred solution of 2-chloro-5-nitrobenzaldehyde (1,
0.05 mol) and Et3N (0.06 mol) in 70 cm3 CH2Cl2 were
added hydrochloride of amino acid ester 2b, 2c, 2f
(0.06 mol) and 5 g MgSO4. The reaction mixture was
stirred for 10 h, filtered, washed with brine, dried, and
evaporated in vacuo. The residue was quenched with i-
PrOH and triturated. The precipitate was collected by fil-
tration, dried, and crystallized to give compounds 3b, 3c, 3f
in 58–91 % yields.
Methyl N-(2-chloro-5-nitrobenzylidene)-b-alaninate
(3b, C11H11ClN2O4)
Yield 91 %; m.p.: 66–67 °C (i-PrOH); 1H NMR: d = 2.73
(t, J = 6.4 Hz, 2H, CH2CO2), 3.64 (s, 3H, CH3), 3.93 (t,
J = 6.4 Hz, 2H, C=NCH2), 7.75 (d, J = 8.4 Hz, 1H, H-3),
8.26 (dd, J = 8.4, 2.8 Hz, 1H, H-4), 8.69 (d, J = 2.8 Hz,
1H, H-6), 8.73 (s, 1H, CH=N) ppm; 13C NMR: d = 36.1,
52.1, 56.5, 123.1, 126.9, 132.3, 134.4, 140.8, 147.3, 157.3,
Fig. 3 Molecular structure of compound 8a according to X-ray
diffraction data. Thermal ellipsoids are drawn at 50 % probability
level
ꢀ
172.5 ppm; IR (KBr): m = 1,741 (C=O), 1,635 (C=N),
1,525 (NO2), 1,348 (NO2) cm-1
.
Methyl 4-[[(1E)-(2-chloro-5-nitrophenyl)
methylene]amino]butanoate (3c, C12H13ClN2O4)
Yield 88 %; m.p.: 61–62 °C (i-PrOH); 1H NMR: d = 1.98
(quin, J = 6.8 Hz, 2H, CCH2C), 2.41 (t, J = 6.8 Hz, 2H,
CH2CO2), 3.62 (s, 3H, CH3), 3.72 (t, J = 6.8 Hz, 2H,
NCH2), 7.75 (d, J = 8.8 Hz, 1H, H-3), 8.26 (dd, J = 8.8,
2.8 Hz, 1H, H-4), 8.69 (s, 1H, CH=N), 8.71 (d, J = 2.8 Hz,
1H, H-6) ppm; 13C NMR: d = 25.9, 31.5, 51.6, 60.0,
122.8, 126.4, 132.0, 134.2, 140.4, 147.0, 156.2, 173.5 ppm;
ꢀ
IR (KBr): m = 1,734 (C=O), 1,634 (C=N), 1,522 (NO2),
1,349 (NO2) cm-1
.
Methyl N-(2-chloro-5-nitrobenzylidene)phenylalaninate
(3f, C17H15ClN2O4)
Fig. 4 Molecular structure of compound 8b according to X-ray
diffraction data. Thermal ellipsoids are drawn at 50 % probability
level
Yield 58 %; m.p.: 103–105 °C (n-PrOH); 1H NMR:
d = 3.07 (m, 1H), 3.31 (m, 1H), 3.68 (s, 3H, CH3), 4.60
(m, 1H), 7.21 (m, 5H, C6H5), 7.80 (d, J = 8.8 Hz, 1H, H-
3), 8.29 (dd, J = 2.8, 8.8 Hz, 1H, H-4), 8.45 (s, 1H,
CH=N), 8.62 (d, J = 2.8 Hz, 1H, H-6) ppm; 13C NMR:
d = 39.2, 52.4, 73.1, 122.8, 126.9, 127.0, 128.6, 129.9,
132.0, 133.7, 137.3, 140.6, 147.0, 158.9, 171.4 ppm; IR
Experimental
All commercially available chemicals were purchased from
Aldrich (St. Louis, MO, USA) and Merck (Darmstadt,
Germany). IR spectra were obtained on a Perkin Elmer BX
The
II spectrometer in KBr tablets and are reported in cm-1
.
ꢀ
(KBr): m = 1,743 (C=O), 1,644 (C=N), 1,522 (NO2), 1,347
1H and 13C NMR spectra of DMSO-d6 solutions with TMS
as an internal standard were recorded on a Varian Mercury
400 spectrometer at 400.45 and 100.61 MHz, respectively.
Elemental analyses were determined on a Vario MICRO
cube CHNOS elemental analyzer. Melting points were
measured with a small Boetius apparatus equipped with a
VEB Analytic RNMK apparatus. Purity of the compounds
synthesized was monitored by TLC on Silufol UV-254
plates with 9:1 chloroform–methanol as eluent.
(NO2) cm-1
.
Preparation of esters of N-(2-chloro-5-
nitrobenzyl)amino acids 4 (reduction)
To a stirred at 0 °C solution of Schiff base 3b, 3c, 3f
(0.05 mol) in 90 cm3, MeOH was added to NaBH4
(0.05 mol) by portions. The reaction mixture was stirred
for 5 h, evaporated and quenched with water. The product
123

Synthesis of N-carboxyalkyl-1,4-benzothiazepine-3(2H)-one derivatives
Methyl N-(2-chloro-5-nitrobenzyl)alaninate hydrochloride
(4d, C11H14Cl2N2O4)
was extracted with CH2Cl2. After being dried over MgSO4,
removal of the solvent in vacuo gave oil. To the oil, 20 cm3
i-PrOH and 6 cm3 HCl were added. The precipitate was
collected by filtration, washed with i-PrOH and dried to
give the title compounds 4b, 4c, 4f (yield 48–78 %).
M.p.: 157–159 °C (i-PrOH); 1H NMR: d = 1.65 (d,
J = 7.2 Hz, 3H, CH3), 3.81 (s, 3H, OCH3), 4.24 (q,
J = 7.2 Hz, 1H, CH), 4.44 (s, 2H, CH2), 7.77 (d,
J = 8.0 Hz, 1H, H-3), 8.26 (d, J = 8.0 Hz, 1H, H-4),
8.87 (s, 1H, H-6), 10.63 (br s, 2H, NH2) ppm; 13C NMR:
d = 34.7, 46.3, 53.5, 55.7, 125.8, 127.5, 131.6, 133.8,
Preparation of esters of N-(2-chloro-5-
nitrobenzyl)amino acids 4 (alkylation)
ꢀ
141.3, 146.8, 171.3 ppm; IR (KBr): m = 1,752 (C=O),
1,534 (NO2), 1,349 (NO2) cm-1
.
To a stirred solution of 2-chloro-5-nitrobenzylchloride (6,
0.05 mol) and hydrochloride of amino acid ester 2a–2f
(0.06 mol) in DMF were added 0.15 mol Et3N and
0.05 mol NaI. The reaction mixture was stirred at
80–90 °C for 15 h and evaporated in vacuo. The residue
was quenched with water and extracted with CH2Cl2. The
organic layer was dried over MgSO4 and evaporated at
reduced pressure. To the residue, 20 cm3 i-PrOH and
6 cm3 HCl were added. The precipitate was collected by
filtration, washed with i-PrOH, and dried to give the
respective compounds 4a–4f in 58–86 % yields. Yields of
esters 4a–4f for both methods are shown in Table 1.
Ethyl N-(2-chloro-5-nitrobenzyl)leucinate
(4e, C15H21ClN2O4)
M.p.: 53–55 °C (i-PrOH); 1H NMR: d = 0.91 (dd,
J = 19.6, 6.4 Hz, 6H, CH(CH3)2), 1.25 (t, J = 6.8 Hz,
3H, CH2CH3), 1.47 (m, 2H, CHCH2CH), 1.85 (m, 1H,
CH2CH(CH3)2), 3.20 (t, J = 6.8 Hz, 1H, NCH), 3.71 (d,
J = 16 Hz, 1H, CHHN), 3.93 (d, J = 16 Hz, 1H, CHHN),
4.01 (q, J = 6.8 Hz, 2H, CH2CH3), 7.63 (d, J = 8.4 Hz,
1H, H-3), 8.09 (dd, J = 8.4, 2.4 Hz, 1H, H-4), 8.43 (d,
J = 2.4 Hz, 1H, H-6) ppm; 13C NMR: d = 14.8, 22.5,
23.5, 25.1, 42.8, 48.5, 59.6, 60.5, 123.4, 124.6, 130.7,
ꢀ
140.0, 140.8, 147.0, 175.2 ppm; IR (KBr): m = 1,736
Methyl N-(2-chloro-5-nitrobenzyl)glycinate hydrochloride
(C=O), 1,521 (NO2), 1,344 (NO2) cm-1
.
(4a, C10H12Cl2N2O4)
1
M.p.: 175–177 °C (i-PrOH); H NMR: d = 3.80 (s, 3H,
Methyl N-(2-chloro-5-nitrobenzyl)phenylalaninate
CH3), 4.02 (s, 2H, CH2), 4.45 (s, 2H, CH2), 7.77 (d,
J = 8.8 Hz, 1H, H-3), 8.25 (dd, J = 8.8, 2.8 Hz, 1H, H-4),
8.81 (d, J = 2.8 Hz, 1H, H-6), 10.45 (br s, 2H, NH2) ppm;
13C NMR: d = 48.0, 48.4, 52.9, 125.3, 126.6, 131.5, 135.4,
hydrochloride (4f, C17H18Cl2N2O4)
1
M.p.: 199–201 °C (n-PrOH); H NMR: d = 3.14 (m, 1H),
3.53 (m, 1H), 3.59 (s, 3H, CH3), 4.30–4.40 (m, 3H), 7.27
(m, 5H, C6H5), 7.84 (d, J = 8.8 Hz, 1H, H-9), 8.27 (d,
J = 8.8 Hz, 1H, H-8), 8.74 (s, 1H, H-6), 10.2 (br s, 2H,
NH2) ppm; 13C NMR: d = 46.5, 46.8, 53.2, 61.5, 125.9,
127.8, 127.9, 129.2, 129.9, 131.6, 133.0, 135.9, 141.5,
ꢀ
140.9, 147.0, 169.7 ppm; IR (KBr): m = 1,744 (C=O),
1,526 (NO2), 1,345 (NO2) cm-1
.
Methyl N-(2-chloro-5-nitrobenzyl)-b-alaninate
ꢀ
148.8, 172.1 ppm; IR (KBr): m = 1,745 (C=O), 1,527
hydrochloride (4b, C11H14Cl2N2O4)
(NO2), 1,347 (NO2) cm-1
.
M.p.: 201–203 °C (i-PrOH); 1H NMR: d = 2.93 (t,
J = 7.6 Hz, 2H, CH2CO2), 3.25 (t, J = 7.6 Hz, 2H,
NCH2CH2), 3.68 (s, 3H, CH3), 4.38 (s, 2H, CH2N), 7.77
(d, J = 8.4 Hz, 1H, H-3), 8.25 (dd, J = 8.4, 2.4 Hz, 1H,
H-4), 8.79 (d, J = 2.4 Hz, 1H, H-6), 10.15 (br s, 2H, NH2)
ppm; 13C NMR: d = 31.0, 43.1, 47.3, 52.1, 125.4, 126.7,
131.3, 133.4, 140.8, 146.6, 171.0 ppm; IR (KBr):
Preparation of (7-nitro-3-oxo-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)carboxylic acids 9 and esters 8
To a stirred solution of N-(2-chloro-5-nitrobenzyl)amino
acid hydrochloride 4a–4f (0.05 mol) and 20.9 cm3 Et3N
(0.15 mol) in 25 cm3 DMSO was added 4.5 cm3 methyl
thioglycolate (0.05 mol). After being stirred at 60 °C for
5 h, the reaction mixture was evaporated, quenched with
250 cm3 water, and extracted with CH2Cl2. The extract
was washed with brine. After being dried over MgSO4,
removal of the solvent in vacuo gave the oil. This oil was
taken up in 50 cm3 of o-xylene, and the solution was
refluxed for 3 h. The solvent was evaporated in vacuo. The
residue was quenched with an aqueous solution of
NaHCO3. The precipitate was collected by filtration,
washed with H2O, and dried to give esters 8a, 8b, 8d, 8e.
The filtrate was stirred with C act., filtered, and acidified
-1
ꢀ
m = 1,747 (C=O), 1,529 (NO2), 1,347 (NO2) cm
.
Methyl 4-[(2-chloro-5-nitrobenzyl)amino]butanoate
hydrochloride (4c, C11H14Cl2N2O4)
1
M.p.: 155–157 °C (i-PrOH); H NMR: d = 1.97 (m, 2H,
CH2), 2.47 (t, J = 6.8 Hz, 2H, CH2), 3.05 (t, J = 7.2 Hz,
2H, CH2), 3.61 (s, 3H, CH3), 4.37 (s, 2H, CH2), 7.87 (d,
J = 8.8 Hz, 1H, H-3), 8.28 (d, J = 8.8 Hz, 1H, H-4), 8.74
(s, 1H, H-6), 9.70 (br s, 2H, NH2) ppm; 13C NMR:
d = 21.6, 30.9, 47.0, 47.2, 52.2, 126.0, 127.5, 131.7, 132.7,
ꢀ
141.3, 146.9, 173.3 ppm; IR (KBr): m = 1,738 (C=O),
1,525 (NO2), 1,347 (NO2) cm-1
.
123

T. M. Tarasiuk et al.
(d, J = 8.8 Hz, 1H, H-9), 7.97 (d, J = 8.8 Hz, 1H, H-8),
8.21 (s, 1H, H-6), 12.53 (br s, 1H, CO2H) ppm; 13C NMR:
d = 32.5, 48.3, 51.5, 123.1, 125.8, 127.9, 133.3, 144.5,
145.8, 168.3, 170.6 ppm; IR (KBr): mꢀ = 1,717 (C=O),
with HCl to pH 6. The precipitate was filtered, washed with
H2O, and dried to obtain acids 9a–9c, 9e, 9f.
Methyl
(7-nitro-3-oxo-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)acetate (8a, C12H12N2O5S)
1,653 (C=O), 1,518 (NO2), 1,339 (NO2) cm-1
.
Yield 68 %; m.p.: 171–173 °C (i-PrOH); 1H NMR:
d = 3.62 (s, 3H, CH3), 4.14 (s, 2H, CH2), 4.19 (s, 2H, 2-
CH2), 4.89 (s, 2H, 5-CH2), 7.32 (d, J = 8.4 Hz, 1H, H-9),
7.97 (d, J = 8.4 Hz, 1H, H-8), 8.18 (s, 1H, H-6) ppm; 13C
NMR: d = 32.1, 48.5, 51.4, 52.5, 123.5, 125.8, 128.2,
133.3, 144.4, 146.0, 168.9, 170.0 ppm; IR (KBr):
3-(7-Nitro-3-oxo-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)propanoic acid (9b, C12H12N2O5S)
1
Yield 24 %; m.p.: 189–191 °C (H2O); H NMR: d = 2.41
(t, J = 7.2 Hz, 2H, CH2), 3.58 (t, J = 7.2 Hz, 2H, CH2),
4.05 (s, 2H, 2-CH2), 4.82 (s, 2H, 5-CH2), 7.31 (d,
J = 8.8 Hz, 1H, H-9), 7.97 (dd, J = 8.8, 2.4 Hz, 1H, H-
8), 8.21 (d, J = 2.4 Hz, 1H, H-6), 12.08 (br s, 1H, CO2H)
ppm; 13C NMR: d = 32.3, 33.0, 42.7, 50.5, 123.3, 125.4,
128.0, 133.5, 144.2, 145.5, 167.9, 172.8 ppm; IR (KBr):
ꢀ
m = 1,748 (C=O), 1,660 (C=O), 1,522 (NO2), 1,344
(NO2) cm-1
.
Methyl 3-(7-nitro-3-oxo-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)propanoate (8b, C13H14N2O5S)
Yield 65 %; m.p.: 141–143 °C (i-PrOH); 1H NMR: 2.48 (t,
J = 7.2 Hz, 2H, CH2), 3.56 (s, 3H, CH3), 3.62 (t,
J = 7.2 Hz, 2H, CH2), 4.05 (s, 2H, 2-CH2), 4.82 (s, 2H,
5-CH2), 7.31 (d, J = 8.4 Hz, 1H, H-9), 7.97 (dd, J = 8.4,
2.4 Hz, 1H, H-8), 8.22 (d, J = 2.4 Hz, 1H, H-6) ppm; 13C
NMR: d = 32.5, 33.0, 43.0, 50.7, 52.0, 123.6, 125.8,
128.3, 133.7, 144.5, 145.9, 168.4, 172.0 ppm; IR (KBr):
ꢀ
m = 1,740 (C=O), 1,645 (C=O), 1,517 (NO2), 1,340 (NO2)
cm-1
.
4-(7-Nitro-3-oxo-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)butanoic acid (9c, C13H14N2O5S)
1
Yield 76 %; m.p.: 170–172 °C (H2O); H NMR: d = 1.65
(m, 2H, CH2), 2.09 (t, J = 6.4 Hz, 2H, CH2), 3.36 (t,
J = 6.4 Hz, 2H, CH2), 4.13 (s, 2H, 2-CH2), 4.81 (s, 2H, 5-
CH2), 7.38 (d, J = 8.0 Hz, 1H, H-9), 7.98 (d, J = 8.0 Hz,
1H, H-8), 8.25 (s, 1H, H-6), 12.08 (br s, 1H, CO2H) ppm;
13C NMR: d = 23.9, 31.3, 32.6, 45.8, 50.4, 123.6, 125.7,
128.3, 133.9, 144.5, 145.9, 168.3, 174.6 ppm; IR (KBr):
ꢀ
m = 1,741 (C=O), 1,656 (C=O), 1,516 (NO2), 1,339 (NO2)
cm-1
.
Methyl 2-(7-nitro-3-oxo-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)propanoate (8d, C13H14N2O5S)
Yield 60 %; m.p.: 121–123 °C (i-PrOH); 1H NMR:
d = 1.33 (d, J = 7.2 Hz, 3H, CH3), 3.52 (s, 3H, OCH3),
3.85 (d, J = 14.0 Hz, 1H), 4.36 (d, J = 14.0 Hz, 1H), 4.77
(d, J = 17.2 Hz, 1H), 4.93 (m, 2H), 7.31 (d, J = 8.4 Hz,
1H, H-9), 7.96 (d, J = 8.4 Hz, 1H, H-8), 8.21 (s, 1H, H-6)
ppm; 13C NMR: d = 15.7, 32.2, 48.5, 52.5, 53.9, 123.4,
125.6, 128.3, 134.1, 144.5, 145.7, 169.0, 171.9 ppm; IR
(KBr): mꢀ = 1,729 (C=O), 1,656 (C=O), 1,510 (NO2), 1,333
ꢀ
m = 1,741 (C=O), 1,631 (C=O), 1,516 (NO2), 1,340 (NO2)
cm-1
.
4-Methyl-2-(7-nitro-3-oxo-2,3-dihydro-1,4-benzothiazepin-
4(5H)-yl)pentanoic acid (9e, C15H18N2O5S)
1
Yield 40 %; m.p.: 238–240 °C (H2O); H NMR: d = 0.52
(d, J = 6.4 Hz, 3H, CH3), 0.80 (d, J = 6.4 Hz, 3H, CH3),
0.99 (m, 1H, CH(CH3)2), 1.57–1.80 (m, 2H, CH2), 3.54 (d,
J = 14.0 Hz, 1H), 4.57 (d, J = 17.6 Hz, 1H), 4.71 (d,
J = 14.0 Hz, 1H), 5.07 (dd, J = 11.2, 2.8 Hz, 1H), 5.14
(d, J = 17.6 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.95 (d,
J = 8.8 Hz, 1H), 8.25 (s, 1H), 12.61 (br s, 1H, CO2H)
ppm; 13C NMR: d = 21.7, 23.3, 24.7, 32.4, 38.7, 48.0,
55.3, 122.9, 125.6, 127.9, 134.1, 144.6, 145.5, 169.8,
(NO2) cm-1
.
Ethyl 4-methyl-2-(7-nitro-3-oxo-2,3-dihydro-1,4-
benzothiazepin-4(5H)-yl)pentanoate (8e, C17H22N2O5S)
Yield 50 %; m.p.: 116–118 °C (i-PrOH); 1H NMR:
d = 0.57 (d, J = 5.6 Hz, 3H, CH3), 0.78 (d, J = 5.6 Hz,
3H, CH3), 1.04 (m, 4H), 1.58–1.88 (m, 2H, CH2), 3.91 (m,
3H), 4.60 (d, J = 12.4 Hz, 1H), 4.73 (d, J = 17.2 Hz, 1H),
5.08 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H, H-9), 7.99 (d,
J = 8.4 Hz, 1H, H-8), 8.34 (s, 1H, H-6) ppm; 13C NMR:
d = 14.1, 21.4, 23.0, 24.3, 31.7, 37.7, 47.5, 55.3, 61.1,
122.9, 125.5, 128.0, 133.7, 144.2, 145.5, 169.7, 171.0 ppm;
ꢀ
173.0 ppm; IR (KBr): m = 1,728 (C=O), 1,623 (C=O),
1,519 (NO2), 1,339 (NO2) cm-1
.
2-(7-Nitro-3-oxo-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)-3-phenylpropanoic acid (9f, C18H16N2O5S)
1
Yield 57 %; m.p.: 238–240 °C (H2O); H NMR: d = 3.11
(d, J = 14.0 Hz, 1H), 3.23 (dd, J = 3.6, 14.0 Hz, 1H),
4.02 (d, J = 14.4 Hz, 1H), 4.15 (d, J = 14.4 Hz, 1H), 4.69
(d, J = 17.6 Hz, 1H), 4.86 (d, J = 17.6 Hz, 1H), 4.97 (m,
1H), 6.92 (m, 5H, C6H5), 7.16 (d, J = 8.8 Hz, 1H, H-9),
7.83 (d, J = 8.8 Hz, 1H, H-8), 7.93 (s, 1H, H-6), 12.85 (br
s, 1H, CO2H) ppm; 13C NMR: d = 32.2, 34.8, 50.5, 61.4,
122.9, 125.7, 126.4, 127.8, 128.4, 129.1, 133.4, 138.2,
ꢀ
IR (KBr): m = 1,722 (C=O), 1,649 (C=O), 1,519 (NO2),
1,336 (NO2) cm-1
.
(7-Nitro-3-oxo-2,3-dihydro-1,4-benzothiazepin-4(5H)-
yl)acetic acid (9a, C11H10N2O5S)
1
Yield 25 %; m.p.: 223–225 °C (H2O); H NMR: d = 4.08
(s, 2H, CH2), 4.13 (s, 2H, 2-CH2), 4.85 (s, 2H, 5-CH2), 7.31
123

Synthesis of N-carboxyalkyl-1,4-benzothiazepine-3(2H)-one derivatives
144.4, 145.6, 169.5, 172.2 ppm; IR (KBr): mꢀ = 1,734
Crystal data for 8b at 293 K: C13H14N2O5S, M = 310.32,
(C=O), 1,619 (C=O), 1,519 (NO2), 1,339 (NO2) cm-1
.
˚
a = 9.5672(8) A, b = 15.2463(11) A, c = 9.9204(8) A,
˚
˚
3
˚
b = 102.024(8)°, V = 1,415.29(19) A , space group P21/c,
Z = 4, Dc = 1.456 g cm-3
,
l(MoKa) = 0.252 mm-1
,
X-ray diffraction study of compounds 8a and 8b
F(000) = 648. 10,070 reflections measured up to
2hmax = 50.0°, 2,483 unique (Rint = 0.0535), which were
used in all calculations. Refinement was converged at
wR2 = 0.1971 (all data), R1 = 0.0666 (1,748 reflections
with I [ 2r(I)), GoF = 1.04.
Intensities of reflections were measured on an automatic
«Xcalibur 3» diffractometer (graphite monochromated
MoKa radiation, CCD-detector, x scanning). All structures
were solved by the direct method using SHELX97 package
[15]. Positions of the hydrogen atoms were located from
electron density difference maps and refined by ‘‘riding’’
model with Uiso = nUeq of a carrier non-hydrogen atom
(n = 1.5 for methyl group and n = 1.2 for other hydrogen
atoms). Full-matrix least-squares refinement against F2 was
performed for non-hydrogen atoms using anisotropic
approximation. Final atomic coordinates, geometrical
parameters, and crystallographic data have been deposited
with the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge, CB2 1EZ, UK (fax: ?44-1223-
336033; e-mail: deposit@ccdc.cam.ac.uk). CCDC dep.
numbers for structures 8a and 8b are 918768 and 918767,
respectively. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/products/csd/request/.
References
1. Levai A (1986) Chem Heterocycl Compd 11:1161
2. Levai A (2000) J Heterocycl Chem 37:199
3. Bariwal JB, Upadhyay KD, Manvar AT, Trivedi JC, Singh JS,
Jain KS, Shah AK (2000) Eur J Med Chem 43:2279
4. Levai A, Kiss-Szikszai A (2008) Arkivoc (i):65
5. Maruenda H, Johnson F (1995) J Med Chem 38:2145
6. Kataoka T, Nakamura Y, Matsumoto H, Iwama T, Shimizu H,
Maruoka O, Tanabe G (1997) Chem Pharm Bull 45:265
7. Neo AG, Marcos CF, Marcaccini F, Pepino R (2005) Tetrahedron
Lett 46:7977
8. Kamei K, Maeda N, Nomura K, Shibata M, Katsuragi-Ogino R,
Koyama M, Nakajima M, Inoue T, Ohno T, Tatsuoka T (2006)
Bioorg Med Chem 14:1978
9. Volovnenko TA, Tarasyuk TN, Volovenko YuM (2011) Zh Org
Farm Khim 9:60
Crystal data for 8a at 293 K: C12H12N2O5S,
10. Volovnenko TA, Tarasiuk TN, Volovenko YuM, Tkachuk TM
(2011) Chem Heterocycl Compd 47:1043
11. Inada Y, Itoh K, Kamiya K, Sugihara H, Nishikawa K (1988) Jpn
J Pharmacol 47:135
˚
M = 296.30, a = 15.4768(5) A, b = 7.9854(3) A,
˚
3
˚
˚
c = 22.1580(7) A, b = 105.811(3)°, V = 2,634.86(15) A ,
space group C2/c, Z = 8,
Dc = 1.494 g cm-3
,
l(MoKa) = 0.267 mm-1, F(000) = 1,232. 14,990 reflec-
tions measured up to 2hmax = 60.0°, 3,814 unique
(Rint = 0.0175) which were used in all calculations.
Refinement was converged at wR2 = 0.1190 (all data),
R1 = 0.0430 (2,911 reflections with I [ 2r(I)),
GoF = 1.06.
12. Amblard M, Daffix I, Bedos P, Berge G, Pruneau D, Paquet J-L,
Luccarini J-M, Belichard P, Dodey P, Martinez J (1999) J Med
Chem 42:4185
13. Park K-H, Olmstead MM, Kurth MJ (1998) J Org Chem 63:113
´
14. Alajarın M, Lopez-Leonardo C, Berna J (2006) Tetrahedron
62:6190
15. Sheldrick G (2008) Acta Crystallogr Sect A 64:112
123