Synthesis of 4-octyl-2H-1,4-benzo-thiazin-3-ones

Article abstract of DOI:10.1016/S0223-5234(03)00127-2

Synthesis, physical and analytical properties of 6-alkylacylamino-4-octyl-2H-1,4-benzo-thiazin-3-ones derivatives are described. These new compounds were prepared by acylation and/or alkylation of the amino group under phase transfer catalysis conditions.

Full text of DOI:10.1016/S0223-5234(03)00127-2

European Journal of Medicinal Chemistry 38 (2003) 769Á773
/
www.elsevier.com/locate/ejmech
Short communication
Synthesis of 4-octyl-2H-1,4-benzo-thiazin-3-ones
Vera L. de M. Guarda a,b, Monique Perrissin a, Francois Thomasson a,
¸
Eulalia A. Ximenes c, Suely L. Galdino c, Ivan R. Pitta c, Cuong Luu-Duc a,
Jacques Barbe d,*
a Laboratoire de chimie pharmacie, UPRESA CNRS 5077, Universite´ Joseph-Fourier, Grenoble I, 38706, La Tronche Cedex, France
b Departamento de Farma´cia/Escola de Farma´cia, Universidade Federal de Ouro Preto, 35400-000 Ouro Preto, Minas Gerais, Brazil
c Departamento de Antibio´ticos, Universidade Federal de Pernambuco, 50670-901 Recife, Pernambuco, Brazil
d GERCTOPÁ
/
UMR CNRS 6009, Universite´ de la Me´diterrane´e, faculte´ de pharmacie, 27, bd Jean-Moulin, 13385 Marseille Cedex 5, France
Received 20 January 2003; received in revised form 23 May 2003; accepted 26 May 2003
Abstract
Synthesis, physical and analytical properties of 6-alkylacylamino-4-octyl-2H-1,4-benzo-thiazin-3-ones derivatives are described.
These new compounds were prepared by acylation and/or alkylation of the amino group under phase transfer catalysis conditions.
Acid hydrolysis of the alkylacylamino-2H-1,4-benzo-thiazin-3-ones afforded N-alkylamino-benzothiazin-3-ones. Some of these
compounds were evaluated in vitro for possible bacteriostatic activity.
´
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: 1,4-Benzothiazines; Antibacterials
1. Introduction
were tested against a lot of microorganisms including
cocci, gram positive and gram-negative bacteria.
Chemical and pharmacological properties of phe-
nothiazines and 1,4-benzothiazines have been widely
studied since a long time [1]. In particular, some
benzothiazines exhibit convincing antifungal activity
2. Chemistry
[2Á4] but moderate antimicrobial activity [5,6]. With
/
2H-1,4-benzothiazin derivatives can be prepared in
accordance with the different synthetic pathways re-
ported in literature [1]. Treatment of 2-chloro-5-nitroa-
niline (1), with sodium sulfide and sulfur [7] gave 2-
amino-4-nitrobenzenethiol sodium salt (2), which was
cyclized to 2H-1,4-benzothiazin-3-one (3), with chlor-
oacetic acid. N-alkylation with octyl bromide and KOH
in methanolic solution as a base [8], afforded 4.
Reduction of the nitro group by SnCl2 in acidic medium
[9] gave the corresponding amine e.g. the 6-amino-4-
octyl-2H-1,4-benzothiazin-3-one (5). N-acylation of the
amino group followed by alkylation under phase
transfer catalysis conditions in basic medium [10], led
to the N-alkylacyl derivatives 7a, 7b and 9a, 9b. N-
alkylation was performed in boiling toluene in the
presence of either sodium hydroxide or potassium
the aim to investigate more accurately antibacterial
properties of structurally related compounds, several
6-alkylacylamino-4-octyl-2H-1,4-benzothiazin-3-ones
were synthesized from 2-chloro-5-nitro-aniline. Action
of sodium sulfide and sulfur on this starting compound
led to the 2-amino-4-nitrobenzenethiol sodium salt
which was cyclized in 6-nitro-2H-1,4-benzothiazin-3-
one by using chloroacetic acid. N-alkylation at the 4-
position followed by reduction of the nitro group, led to
6-amino-4-octylbenzothiazin-3-ones. This later deriva-
tive was acylated then alkylated. Sulfuric acid hydrolysis
provided the 6-alkylamino-4-octyl-2H-1,4-benzothia-
zine derivatives. Finally, some test sample compounds
carbonate in excess and 0.5ꢀ
/
10ꢁ3 mol of tetrabuty-
* Corresponding author.
E-mail address: gerctop@pharmacie.univ-mrs.fr (J. Barbe).
lammonium bromide as catalyst. Acidic hydrolysis of 9a
´
0223-5234/03/$ - see front matter # 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
doi:10.1016/S0223-5234(03)00127-2

770
V.L.d.M. Guarda et al. / European Journal of Medicinal Chemistry 38 (2003) 769Á773
/
Fig. 1. 2H-1,4-benzothiazin-3-one derivatives: synthetic pathways.
and 9b afforded the 6-alkylamino-4-octyl-2H-1,4-ben-
zothiazin-3-one derivatives 10a and 10b. Synthetic path-
way is portrayed in Fig. 1.
4. Experimental protocols
4.1. Biology
Bacterial strains were cultivated on MuellerÁHinton
/
agar medium. Inocula were prepared from 18 h old
subcultures at 37 8C in the same broth. Turbidity of the
culture suspension was adjusted to obtain a 0.5 value on
the McFarland scale, i.e. 108 UFG mLꢁ1. Mother
solutions of each compound to be tested were prepared
at the concentration of 1280 mg mLꢁ1 in a mixture of
3. Biological activity
The minimal inhibitory concentration (MIC) against
six different microorganisms was estimated in vitro for
compounds 4Á6, 7a, 7b, 8, 9a, 9b, 10a and 10b. The
/
following strains were used: Micrococcus flavus
(DAUFPE 323), Staphylococcus aureus (IC 06), Salmo-
nella enteritidis (DAUFPE 415), Bacillus cereus
(DAUFPE 11), Escherichia coli (IC 02) and Proteus
vulgaris (IC 03). M. flavus DAUFPE 323, S. enteriditis
DAUFPE 415 and B. cereus DAUFPE 11 strains came
from the collection of the Department of Antibiotics
(UFP-Br). S. aureus IC 06, E. coli IC 02 and P. vulgaris
IC 02 strains are wild strains isolated from contami-
nated foods.
DMSOÁ
/
Tween 80Ádistilled water (1:1:8). Serial dilu-
/
tions were made with sterile distilled water according to
a geometric progression of ratio 2, with the aim to
obtain final concentrations in the range of 128Á0.5 mg
/
mLꢁ1. Moreover, the absence of intrinsic activity
against the microorganisms tested of the 1/10 diluted
DMSO was checked up. Ciprofloxacin was used as
reference antibiotic. Bacterial suspensions were streaked
with a loop of 0.05 mL. After 18 h incubation time at
37 8C, results were compared to those obtained with a
control sample that did not contain drug. MIC was
Results are collected in the Table 1.

V.L.d.M. Guarda et al. / European Journal of Medicinal Chemistry 38 (2003) 769Á
/773
771
Table 1
MIC (mg mLꢁ1) of benzothiazine derivatives
Bacterial strains
4
5
6
7a
7b
8
9a
9b
10a
10b
Ciprofloxacin
M. flavus
S. aureus
S. enteritidis
B. cereus
E. coli
ꢀ
/
128
128
128
128
128
128
ꢀ
/
128
128
128
128
128
128
ꢀ
/
128
128
128
128
128
128
ꢀ
/
128
128
128
128
128
128
ꢀ
/
128
ꢀ
/
128
128
128
128
128
128
ꢀ
/
128
128
128
128
128
128
ꢀ
/
128
128
128
128
128
128
ꢀ
/
128
128
128
128
128
128
ꢀ
/
128
128
128
128
128
128
0.25
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
128
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
4
8
2
2
4
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
16
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
16
32
/
128
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
ꢀ
/
P. vulgaris
ꢀ/
ꢀ/
ꢀ/
ꢀ/
ꢀ/
ꢀ/
ꢀ/
ꢀ/
ꢀ/
defined as the lowest drug concentration with which
there is no bacterial growth [11].
(27.5), 275 (34), 210 (100), 195 (53), 181 (28.3), 149
(25.4), 135 (27.5), 41 (44.3).
4.4. 6-Amino-4-octyl-2H-1,4-benzothiazin-3-one (5)
4.2. Chemistry
Compound 4 (1.13 g, 3.5 mmol) was added portion-
wise, over a 15 min period to a cold and stirred solution
of 3.72 g of stannous chloride dihydrate dissolved in 3.8
mL of concentrated hydrochloric acid. Mixture was left
for 15 min at room temperature before to be refluxed for
2 h. After cooling, precipitate of 6-amino-4-octyl-2H-
Melting points were measured on a Buchi apparatus.
Thin layer chromatography was performed on Merck 60
F254 silica gel plates with a 0.2 mm thickness. Com-
pounds were powdered, mixed with KBr at 1% concen-
tration and pressed into pellets before IR spectra be
recorded on a PerkinÁElmer 1310 spectrometer.
/
1,4-benzothiazin-3-one hydrochloride (m.p. 163Á
/
1H- and 13C-NMR spectra were recorded on a Bruker
AC 200 spectrophotometer. DMSO-d6 was used as
solvent and TMS as the reference. Chemical shifts (d)
are given in parts per million (ppm), and coupling
constants (J) are given in hertz (Hz). The 70 eV
electronic impact mass spectra were recorded on a R-
165 8C) was filtered and put in a suspension in water.
A 20% NaOH solution was added until pH 10, to give
the corresponding amine. The oily compound was
extracted with chloroform (3ꢀ50 mL), washed with
/
10% aq. NaOH and dried over anhydrous magnesium
sulfate. Solvent was evaporated. The crude was purified
1010C DelsiÁ
Elemental analysis experimental values fell in the
range of 90.4% of the required theoretical values.
/Nermag spectrometer.
by column chromatography on silica gel using tolueneÁ
ethyl acetate (8:2) as eluent. Yield, 91%; Rf, 0.61
(tolueneÁ
ethyl acetate, 7:5); IR (n cmꢁ1): 3450, 3350,
2920, 2830, 1650, 1600, 1490, 1380, 1140, 760; 1H-NMR
(d ppm, DMSO-d6): 0.84 (t, CH3, Jꢂ6.6 Hz), 1.23 (m,
CH2 chain, 10H), 1.52 (m, CH2 chain), 3.31 (s, CH2
ring), 3.81 (t, NÃCH2, Jꢂ7.1 Hz), 5.21 (s, NH2), 6.28
(dd, 1H, Jꢂ8.3 and 2.1 Hz), 6.53 (d, 1H, Jꢂ2.1 Hz),
6.98 (d, 1H, Jꢂ
8.3 Hz); 13C-NMR (d ppm, DMSO-d6,
BB decoupling and DEPT): 13.8 (CH3), 22.0 (CH2),
26.0Á28.6 (4CH2), 31.1 or 31.5 (CH2 chain, CH2 ring),
43.4 (CH2ÃN), 103.7 (CH), 107.5 (C), 109.3 (CH) 128.4
/
/
/
Chemical data on 2 and 3 are given in Ref. [12].
/
4.3. 4-Octyl-6-nitro-2H-1,4-benzothiazin-3-one (4)
/
/
Compound 3 (1.05 g, 5 mmol) and potassium
hydroxide (0.56 g, 10 mmol) were dissolved in DMSO
(10 mL) and methanol (12.5 mL). The mixture was
stirred for 10 min before octyl bromide (1.93 g, 10
mmol) was added. Solution was heated at 50 8C with
stirring for 15 h. After cooling, water was added and the
/
/
/
/
/
(CH), 139.7 (C) 148.4 (C), 165 (CO); MS, m/z (%): 292
(100), 180 (52.4), 165 (38.1), 151 (98.5), 135 (32), 41
(52.7).
organic phase was extracted with cyclohexane (3ꢀ
mL) and purified by column chromatography on silica
gel with a mixture of tolueneÁethyl acetate (8:2) as
eluent. Yield, 78%; Rf, 0.85 (tolueneÁethyl acetate, 7:5);
IR (n cmꢁ1): 2920, 2860, 1680, 1525, 1345, 1140, 740;
1H-NMR (d ppm, DMSO-d6): 0.82 (t, CH3, Jꢂ
6.6 Hz),
1.20 (m, CH2 chain, 10H), 1.51 (m, CH2 chain), 3.61 (s,
CH2 ring), 4.05 (t, NÃCH2, Jꢂ7.1 Hz), 7.69 (d, 1H, Jꢂ
8.5 Hz), 7.86 (dd, 1H, Jꢂ8.5 and 2.2 Hz), 7.99 (d, 1H,
Jꢂ
2.2 Hz); 13C-NMR (d ppm, DMSO-d6, BB decou-
pling and DEPT): 13.8 (CH3), 22.0 (CH2 chain), 28.4Á
25.7 (4CH2), 29.7 or 31.0 (CH2 chain, CH2 ring), 43.2
(CH2ÃN), 112.4 (CH), 117.5 (CH), 128.8 (CH), 132.8
(C), 139.2 (C), 146.3 (C), 164.1 (CO); MS, m/z (%): 322
/
50
/
/
4.5. 6-Acetylamino-4-octyl-2H-1,4-benzothiazin-3-one
(6)
/
A mixture of compound 5 (1.46 g, 5 mmol) and acetic
anhydride (10 mL) was refluxed for 10 min. Excess of
anhydride was hydrolyzed with 10 mL of water and the
mixture was then refluxed for 5 min more. The
precipitate obtained was washed with water and recrys-
/
/
/
/
/
/
tallized from ethanolÁ
75Á77 8C; Rf, 0.85 (chloroformÁ
cmꢁ1): 3280, 2920, 2850, 1680, 1600, 1510, 1415, 1320,
/
water mixture. Yield, 78%; m.p.
/
/
/ethanol, 9:1); IR (n

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V.L.d.M. Guarda et al. / European Journal of Medicinal Chemistry 38 (2003) 769Á773
/
1
1
1150, 815; H-NMR (d ppm, DMSO-d6): 0.83 (t, CH3,
Jꢂ6.1 Hz), 1.21 (m, CH2 chain, 10H), 1.53 (m, CH2
chain), 2.04 (s, COCH3), 3.42 (s, CH2 ring), 3.85 (t, NÃ
1395, 1140, 825; H-NMR (d ppm, DMSO-d6): 0.82 (t,
CH3), 0.85 (t, CH3), 1.17Á1.40 (m, CH2, 16H), 1.76 (s,
COCH3), 3.50 (s, CH2 ring), 3.62 (t, NÃCH2), 4.01 (t,
NÃCH2), 6.95 (dd, CH, Jꢂ8.1 and 1.4 Hz), 7.26 (broad
s, CH), 7.44 (d, CH, Jꢂ
8.1 Hz); 13C-NMR (d ppm,
DMSO-d6, BB decoupling and DEPT): 13.6 (CH3), 13.8
(CH3). 19.4 (CH2), 21.9 (CH2), 22.5 (COCH3), 25.6Á
28.4 (4CH2), 29.4 (CH2), 30.3 (CH2), 31 (CH2), 42.5
(NÃCH2), 47.6 (NÃCH2), 118.4 (CH), 122.5 (CH), 122.8
/
/
/
/
CH2, Jꢂ
/
7.4 Hz), 7.22 (broad d, CH), 7.30 (d, CH), 7.68
/
/
(broad d, CH), 10.15 (s, NH); 13C-NMR (d ppm,
DMSO-d6, BB decoupling and DEPT): 13.8 (CH3), 22
/
(CH2), 24 (CH3) 28.5Á
chain, CH2 ring), 43.6 (NÃ
(CH), 116.4 (C) 128 (CH), 138.7 (C), 139.1 (C), 164.7
(CO), 168.4 (COCH3); MS, m/z (%): 334 (70.7), 287
(23.1), 222 (26), 207 (31.6), 180 (76.8), 165 (26.9), 151
(100), 43 (85.4).
/25.9 (4CH2), 30.7 or 31.1 (CH2
/
/CH2), 108.6 (CH), 113.7
/
/
(C), 128.8 (CH), 139.3 (C), 141.7 (C), 164.4 (CO), 168.6
(NCO); MS, m/z (%): 390 (85.3), 305 (66.5), 193 (57.8),
98 (91.1), 43 (100).
4.6. 6-Acetylalkylamino-4-octyl-2H-1,4-benzothiazin-3-
one (7)
4.9. 6-Benzoylamino-4-octyl-2H-1,4-benzothiazin-3-one
(8)
A mixture of compound 6 (1.67 g, 5 mmol), potassium
carbonate (1.4 g), NaOH (7 g) and tetrabutylammonium
bromide (0.16 g) was refluxed in toluene (100 mL).
Solution of ethyl iodide (or butyl bromide) (7.5 mmol)
in toluene (10 mL) was added. Reflux with stirring was
continued for 4 h. After cooling, the mixture was filtered
and water was added to the filtrate. The organic phase
Benzoyl chloride (2 mL) was added drop-wise to a
suspension of 5 (1.46 g, 5 mmol) in 5% aq. NaOH (20
mL). Mixture was stirred for 10 min. The precipitate
obtained was washed with water before to be recrys-
tallized from 95% ethanol. Yield, 48%; m.p., 93Á
Rf, 0.68 (tolueneÁ
ethyl acetate, 6:4); IR (n cmꢁ1): 3300,
2920, 2840, 1655, 1645, 1590, 1410, 1300, 1140, 850; 1H-
NMR (d ppm, DMSO-d6): 0.83 (t, CH3), 1.20Á1.25 (m,
CH2, 10H), 1.52 (m, CH2), 3.45 (s, CH2 ring), 3.91 (t,
NÃCH2), 7.35 (d, CH, Jꢂ8.4 Hz), 7.51 (dd, CH), 7.52Á
7.56 (m, C6H5, 3CH), 7.83 (d, CH, Jꢂ1.7 Hz), 7.95 (dd,
C6H5, 2CH, Jꢂ
7.9 and 1.3 Hz), 10.30 (s, NH); 13C-
NMR (d ppm, DMSO-d6, BB decoupling and DEPT):
13.8 (CH3), 22 (CH2), 25.9Á31.1 (5CH2) and (CH2 ring),
43.6 (NÃCH2), 109.9 (CH), 115 (CH), 117.4 (C), 128.1
/
95 8C;
/
was separated, washed with water (2ꢀ/50 mL), dried
/
over anhydrous magnesium sulfate before the solvent
was evaporated. Crude was purified by column chro-
matography on silica gel.
/
/
/
/
/
4.7. 6-Acetylethylamino-4-octyl-2H-1,4-benzothiazin-3-
one (7a)
/
/
The product was purified by column chromatography
(CH), 128.3 (2CH, C6H5), 127.6 (2CH, C6H5), 131.6
(CH, C6H5), 134.7 (C, C6H5), 138.5 (C), 139.1 (C), 164.6
(CO), 165.6 (CO); MS, m/z (%): 396 (26), 269 (9.5), 152
(8.8), 105 (100), 77 (37.5).
on silica gel with tolueneÁethyl acetate (1:2) as eluent.
/
Yield, 31%; m.p., 67Á
/
69 8C; Rf, 0.76 (chloroformÁ
/
ethanol, 9:1); IR (n cmꢁ1): 2920, 2850, 1670, 1640,
1595, 1410, 1360, 1135, 840; 1H-NMR (d ppm, DMSO-
d6): 0.81 (t, CH3, Jꢂ
1.17 (m, CH2, 10H), 1.44 (m, CH2 chain), 1.76 (s,
COCH3), 3.51 (s, CH2 ring), 3.61 (q, NÃCH2, Jꢂ7.1
Hz), 4.02 (t, NÃCH2), 6.96 (dd, CH, Jꢂ8.2 and 1.8 Hz),
7.27 (broad s, CH), 7.46 (d, CH, Jꢂ
8.1 Hz); 13C-NMR
(d ppm, DMSO-d6, BB decoupling and DEPT): 12.8
(CH3), 13.8 (CH3), 21.9 (CH2), 22.4 (COCH3), 25.6Á
28.4 (4CH2), 30.3 or 31 (CH2 chain, CH2 ring) 42.5
(NÃCH2), 42.8 (NÃCH2), 118.5 (CH), 122.6 (CH), 122.9
(C), 128.8 (CH), 139.4 (C), 141.4 (C), 164.5 (CO), 168.3
CO); MS, m/z (%): 362 (91), 320 (21.7), 193 (34.4),
/
6.1 Hz), 0.99 (t, CH3, Jꢂ
/
7.6 Hz),
4.10. 6-Benzoylalkylamino-4-octyl-2H-1,4-benzothiazin-
3-one (9)
/
/
/
/
Alkylation under phase transfer catalysis conditions
was used as described above with 7.
/
/
4.11. 6-Benzoylbutylamino-4-octyl-2H-1,4-benzothiazin-
3-one (9a)
/
/
Compound was purified by column chromatography
(NÃ
/
on silica gel with tolueneÁ/ethyl acetate (8:2) as eluent.
179 (23.2), 70 (100), 43 (54.2).
Yield, 78%; viscous liquid; Rf, 0.41 (tolueneÁ
/
ethyl
acetate, 6:4); IR (n cmꢁ1): 2930, 2860, 1670, 1650,
1595, 1390, 1210, 1130, 700; 1H-NMR (d ppm, DMSO-
4.8. 6-Acetylabutylamino-4-octyl-2H-1,4-benzothiazin-3-
one (7b)
d6): 0.83 (t, CH3), 0.86 (t, CH3), 1.08Á
16H), 3.39 (s, CH2 ring), 3.75 (t, NÃCH2), 3.83 (t, NÃ
CH2), 6.87 (dd, CH, Jꢂ8.2 and 1.8 Hz), 7.0 (d, CH, Jꢂ
1.8 Hz), 7.29 (d, CH), 7.19Á
7.31 (m, C6H5, 5H); 13C-
NMR (d ppm, DMSO-d6, BB decoupling and DEPT):
13.7 (CH3), 13.8 (CH3), 19.5 (CH2), 21.9 (CH2), 25.7Á
/1.54 (m, CH2,
/
/
The product was purified by column chromatography
/
/
on silica gel with tolueneÁ
Yield, 65%; m.p., 68Á70 8C; Rf, 0.83 (chloroformÁ
ethanol, 9:1); IR (n cmꢁ1): 2920, 2845, 1655, 1590,
/
ethyl acetate (6:4) as eluent.
/
/
/
/

V.L.d.M. Guarda et al. / European Journal of Medicinal Chemistry 38 (2003) 769Á
/773
773
28.4 (4CH2), 29.2 (CH2), 30.4 (CH2), 31.0 (CH2), 42.6
(NÃCH2), 49.0 (NÃCH2), 118.5 (CH), 121.7 (C), 122.1
(CH), 127.6 (2CH), 128 (2CH), 128.4 (CH), 129.2 (C),
CO);
decoupling and DEPT): 13.7 (CH3), 13.8 (CH3), 19.7
(CH2), 22 (CH2), 26 (CH2), 26.9Á31.5 (6CH2), 42.4 (NÃ
CH2), 43.4 (NÃCH2), 101.8 (CH), 107.3 (CH and C),
128.5 (CH), 139.8 (C), 148.7 (C), 165.0 (CO); MS, m/z
(%): 348 (100), 305 (26.3), 207 (14.1), 193 (20.7), 165
(8.5), 84 (9.4).
/
/
/
/
/
136.5 (C), 138.8 (C), 142 (C), 164.3 (CO), 169 (NÃ
/
MS, m/z (%): 452 (1.2), 160 (9.5), 105 (100), 77 (22).
4.12. 6-Benzoyloctylamino-4-octyl-2H-1,4-benzothiazin-
3-one (9b)
4.15. 6-Octylamino-4-octyl-2H-1,4-benzothiazin-3-one
(10b)
Compound was purified by column chromatography
on silica gel with the mixture tolueneÁethyl acetate (8:2)
/
Compound was recrystallized from methanol. Yield,
as eluent. Yield, 66%; viscous liquid; Rf, 0.75 (tolueneÁ
/
ethyl acetate, 6:4); IR (n cmꢁ1): 2920, 2840, 1670, 1650,
48%; m.p., 73Á
/
75 8C; Rf, 0.67 (tolueneÁethyl acetate,
/
8:2); IR (n cmꢁ1): 3380, 2920, 2840, 1645, 1600, 1510,
1
1590, 1385, 1130, 720; H-NMR (d ppm, DMSO-d6):
1
1360, 1140, 805; H-NMR (d ppm, DMSO-d6): 0.83 (t,
0.83 (t, CH3), 0.84 (t, CH3), 1.08Á
1.50 (m, CH2, 4H), 3.40 (s, CH2 ring), 3.75 (t, NÃ
3.81 (t, NÃCH2), 6.88 (dd, CH, Jꢂ8.2 and 1.9 Hz), 7.0
(d, CH, Jꢂ1.9 Hz), 7.29 (d, CH, Jꢂ8.2 Hz) 7.21Á7.28
(m, C6H5, 5H); 13C-NMR (d ppm, DMSO-d6, BB
decoupling and DEPT): 13.8 (2CH3), 22 (2CH2), 25.7Á
28.6 (8CH2), 30.4 (CH2), 31.1 (CH2), 42.6 (NÃCH2),
49.2 (NÃCH2), 118.5 (CH), 121.7 (C), 122.2 (CH), 127.7
(2CH), 128 (2CH), 128.5 (CH), 129.3 (CH), 136.5 (C),
CO); MS, m/z
/1.21 (m, CH2, 20H),
CH3), 0.84 (t, CH3), 1.20Á
(m, CH2, 4H), 2.97 (dt, NÃ
(t, NÃCH2), 5.73 (t, NH), 6.26 (dd, CH, Jꢂ
Hz), 6.44 (d, CH, Jꢂ2.1 Hz), 7.02 (d, CH, Jꢂ
13C-NMR (d ppm, DMSO-d6, BB decoupling and
DEPT): 13.8 (2CH3), 22.0 (2CH2), 26Á28.6 (8CH2),
31.1 (CH2), 31.2 (CH2), 31.5 (CH2), 42.7 (NÃCH2), 43.4
(NÃCH2), 101.6 (CH), 107.2 (C), 107.4 (CH), 128.4
/
1.24 (m, CH2 20H), 1.48Á
CH2), 3.30 (s, CH2 ring), 3.85
8.4 and 2.1
8.4 Hz);
/
1.54
/
CH2),
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
(CH), 139.8 (C), 148.7 (C), 165 (CO); MS, m/z (%): 404
(100), 305 (62.5), 263(18.9), 193 (50.7), 165(23.7), 41
(42.1).
138.8 (C), 142 (C), 164.3 (CO), 169.1 (NÃ
/
(%): 508 (29.4), 216 (6.5), 105 (100), 77 (23.4), 43 (5.8).
4.13. 6-Alkylamino-4-octyl-2H-1,4-benzothiazin-3-one
(10)
References
Compound 9 (2 mmol) suspended in 70% sulfuric acid
(5 mL) was refluxed at 147Á150 8C for 30 min. After
cooling, water (6 mL) was added and the mixture
poured out into cold water (20 mL). Insoluble part
/
[1] R.R. Gupta, K.G. Ojha, Phenothiazines and 1,4-Benzothiazines:
Chemical and Biochemical Aspects, Elsevier, Amsterdam, 1988,
pp. 163Á
[2] R. Fringuelli, F. Schiafella, F. Bistoni, L. Pitzurra, A. Vecchiar-
elli, Bioorg. Med. Chem. 6 (1998) 103Á108.
[3] R. Fringuelli, F. Schiafella, A. Vecchiarelli, J. Chemother. 13
(2001) 9Á14.
[4] A. Macchiarulo, G. Costantino, D. Fringuelli, A. Vecchiarelli, F.
Schiafella, R. Fringuelli, Bioorg. Med. Chem. 10 (2002) 3415Á
/260.
was extracted with chloroform (2ꢀ20 mL). This
/
/
organic phase was treated with a 28% aqueous solution
of ammonia (10 mL), washed with water and dried over
anhydrous magnesium sulfate. Solvent was evaporated.
The crude compound was triturated with a mixture of
ether petroleum and ethyl acetate, and cooled for 12 h in
the fridge.
/
/
3423.
[5] V. Visokov, V. Charushin, G. Afanasyeva, O. Chupakhin,
Mendeleev comm. 3 (1993) 159Á160.
/
[6] G. Grandolini, V. Ambrogi, L. Baiocchi, M. Giannangeli, A.
Furlani, A. Papaioannou, L. Perioli, V. Scarcia, Heterocycl.
4.14. 6-Butylamino-4-octyl-2H-1,4-benzothiazin-3-one
(10a)
commun. 1 (1995) 265Á
[7] K. Fries, M. Vorbrodt, G. Siebert, Liebigs Ann. Chem. 454 (1927)
121Á124.
[8] L. Ngadi, A.M. Galy, J.P. Galy, J. Barbe, A. Cremieux, J.
Chevalier, D. Sharples, Eur. J. Med. Chem. 25 (1990) 67Á70.
[9] V. Cecchetti, S. Dominici, A. Fravolini, F. Schiaffella, Eur. J.
Med. Chem.-Chim. Ther. 19 (1984) 29Á35.
[10] A. Koziara, S. Zawadzki, Synthesis 7 (1979) 527Á
/
280.
/
Compound was purified by column chromatography
on silica gel with tolueneÁethyl acetate (8:2) as eluent.
/
/
Yield, 68%; m.p., 46Á
/
48 8C; Rf, 0.65 (tolueneÁethyl
/
acetate, 8:2); IR (n cmꢁ1): 3390, 2920, 2850, 1655, 1600,
/
1
1135, 1360, 710; H-NMR (d ppm, DMSO-d6): 0.83 (t,
/529.
[11] P. Courvalin, F. Goldstein, A. Philippon, J. Sirot, L’Antibio-
gramme, MPC/Videom, Paris, 1985, p. 191.
CH3), 0.9 (t, CH3), 1.16Á
CH2), 3.32 (s, CH2 ring), 3.86 (t, NÃ
Jꢂ8.4 and 2.1 Hz), 6.47 (d, CH, Jꢂ
CH, Jꢂ
8.4 Hz); 13C-NMR (d ppm, DMSO-d6, BB
/
1.54 (m, CH2 16H), 2.99 (t, NÃ
CH2), 6.29 (dd, CH,
2.1 Hz), 7.03 (d,
/
/
[12] V.L.M. Guarda, M. Perrissin, F. Thomasson, E.A. Ximenes, S.L.
Galdino, I.R. Pitta, C. Luu-Duc, Heterocycl. Commun. 6 (2000)
/
/
/
49Á54.
/