A simple and efficient synthesis of methyl 3,4-dihydro-2-methyl-2H-1,2- benzothiazine-3-carboxylate 1,1-dioxide from saccharin sodium salt

Article abstract of DOI:10.1055/s-2006-926289

A straightforward synthesis of methyl 3,4-dihydro-2-methyl-2H-1,2- benzothiazine-3-carboxylate 1,1-dioxide from saccharin sodium salt was achieved in five steps. Methyl 3,4-dihydro-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide found application as a precursor for the synthesis of a new class of quaternary ammonium derivatives that are potential antiosteoarthritis agents. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926289

SHORT PAPER
591
A Simple and Efficient Synthesis of Methyl 3,4-Dihydro-2-methyl-2H-1,2-
benzothiazine-3-carboxylate 1,1-Dioxide from Saccharin Sodium Salt
S
ynthesis of Methy
u
l
3,4-dihydr
r
o-2-meth
é
yl-2
H
-1,2-
l
benzot
i
hiazine
e
-3-carboxyl
n
ate 1,1-Dioxide Vidal,* Jean-Claude Madelmont, Emmanuelle Mounetou
INSERM UMR 484, rue Montalembert, BP 184, 63005 Clermont-Ferrand Cedex, France
Fax +33(4)73150801; E-mail: vidal@inserm484.u-clermont1.fr
Received 16 June 2005; revised 26 August 2005
In the first step, saccharin sodium salt was treated with
methyl iodide in DMF to afford 2-methyl-1,2-benzisothi-
azolin-3-one 1,1-dioxide (1) quantitatively.6,7 Lithium
aluminum hydride reduction resulted in the opening of the
Abstract: A straightforward synthesis of methyl 3,4-dihydro-2-
methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide from sac-
charin sodium salt was achieved in five steps. Methyl 3,4-dihydro-
2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide found
application as a precursor for the synthesis of a new class of quater- benzothiazolinone ring and afforded 2-(hydroxymethyl)-
N-methylbenzenesulfonamide (2) in 41% yield.8 Treat-
nary ammonium derivatives that are potential antiosteoarthritis
agents.
ment with 1-methylbromoacetate in DMF in the presence
of sodium hydride gave the acetate derivative 3.9 Bromi-
Key words: oxicams, quaternary ammonium, heterocycles, esters,
enols
nation of 3 with phosphorus tribromide in Et2O–THF
(4:1) afforded 4 in high yield (76%).5,6 The key step in this
synthesis was the intramolecular substitution of 4 in the
Oxicams are commonly used anti-inflammatory agents presence of sodium hydride in DMF to yield methyl 3,4-
(Figure 1).1 Recent work by us showed that the introduc- dihydro-2-methyl-2H-1,2-benzothiazine-3-carboxylate
tion of a quaternary ammonium (QA) moiety in oxicams 1,1-dioxide (5) in 14% overall yield.10
resulted in an increased specific affinity for cartilaginous
tissues.2,3 Additionally, some QA derivatives of oxicams,
particularly QA-propoxicam (Figure 1), were potential
specific antiosteoarthritis agents stimulating the mRNA
expression of aggrecan.4 The C-4 enol function of oxi-
cams is responsible for the anti-inflammatory activity. As
no structure–activity data on QA derivatives was avail-
able, we explored the effects of removing the enol func-
tion on the antiosteoarthritis activity. The new QA-
oxicam analogues prepared were 2H-1,2-benzothiazines
(Scheme 2).
O
O
MeI
LiAlH4
N– Na+
N
THF
41%
DMF
99%
S
S
O2
O2
1
OH
O
O
OH
BrCH2COOMe,
NaH
PBr3
H
DMF
57%
Et2O–THF
4:1
76%
N
N
S
S
O2
O2
2
3
O
Br
O
OH
4
O
OH
O
NaH
O
O
I–
N+
R
N
DMF
77%
N
5
8
N
N
6
7
S
3
N
S
H
H
O2
2
O2
1
S
N
S
4
5
O2
O2
QA-Propoxicam
Oxicams
Scheme 1
Figure 1 Structure of oxicam derivatives and QA-propoxicam
From this key intermediate 5, methyl 2-methyl-2H-1,2-
benzothiazine-3-carboxylate 1,1-dioxide (6) was obtained
in 87% yield by bromination followed by elimination in
the presence of a catalytic amount of dibenzoyl peroxide
and NBS in CH2Cl2–CCl4 (1:5) (Scheme 2).
The synthesis of these new QA derivatives was achieved
starting from methyl 3,4-dihydro-2-methyl-2H-1,2-ben-
zothiazin-3-carboxylate 1,1-dioxide (5). Recently, Wells
et al. described the synthesis of 6,7-substituted 3,4-dihy-
dro-1,2-benzothiazine-3-carboxylate 1,1-dioxide in up to
eight steps from aniline derivatives in poor overall yield.5
In this paper, we describe a convenient method for the
synthesis of compound 5 in a five-step procedure from
saccharin sodium salt with improved yields (Scheme 1).
New QA conjugates were then synthesized by introducing
the QA entity to 5 and 6 via an amide link in a two-step
procedure (Scheme 2). Firstly, reaction of the primary
amino group of 3-(dimethylamino)propylamine with the
ester function of 5 and 6, in xylene at 140 °C, provided the
appropriate amides 7 and 8, respectively.11 In a second
step, these compounds were converted into QA salts 9 and
10 by treatment with excess methyl iodide in acetone in
56% and 35% overall yields, respectively.
SYNTHESIS 2006, No. 4, pp 0591–0593
x
x
.
x
x
.2
0
0
6
Advanced online publication: 11.01.2006
DOI: 10.1055/s-2006-926289; Art ID: T08405SS
© Georg Thieme Verlag Stuttgart · New York

592
A. Vidal et al.
SHORT PAPER
O
O
NBS, dibenzoyl peroxide
O
O
N
N
CH2Cl2–CCl4
(1:5)
S
S
O2
O2
87%
5
6
H2N(CH2)3NMe2
H2N(CH2)3NMe2
51%
67%
xylene
O
xylene
O
N
H
N
N
H
N
N
N
S
S
O2
O2
7
8
MeI
acetone
MeI
acetone
83%
79%
O
O
I–
N+
I–
N+
N
H
N
H
N
N
S
S
O2
O2
9
10
Scheme 2
orated. The residue was purified by column chromatography (silica
gel; CH2Cl2–EtOH, 98:2) to afford pure 3 (1.16 g, 57%) as a white
solid; mp 75–77 °C; Rf 0.26 (CH2Cl2–EtOH, 98:2).
IR (KBr): 3300–3400, 1748, 1323, 1166, 1204 cm–1.
1H NMR (CDCl3): d = 2.87 (s, 3 H, NCH3), 3.33 (s, 1 H, OH), 3.66
(s, 3 H, OCH3), 4.04 (s, 2 H, NCH2), 4.87 (s, 2 H, CH2OH), 7.36–
7.65 (m, 3 H, ArH), 7.91 (d, J = 7.7 Hz, 1 H, ArH).
In conclusion, an efficient synthetic procedure was found
to access 3,4-dihydro-2H-1,2-benzothiazine 5. The meth-
od offers several advantages including inexpensive start-
ing material, mild reaction conditions, and simple
experimental and isolation procedures. Compound 5 was
used as a key intermediate for the preparation of QA de-
rivatives and could be useful for the synthesis of deriva-
tives of potential therapeutic interest with the same
heterocyclic core.
13C NMR (CDCl3): d = 35.8, 50.3, 52.9, 62.4, 128.2, 130.2, 131.6,
134.0, 136.3, 140.9, 169.8.
Methyl 2-[2-(Bromomethyl)-N-methylphenylsulfonamido] Ace-
tate (4)6
Alcohol 3 and PBr3 were reacted according to the known procedure
to afford compound 4 as a white solid; mp 86–88 °C; Rf 0.77
(CH2Cl2–EtOH, 99:1).
Mps are uncorrected and were determined in glass capillary tubes
with an electrothermal digital apparatus. Analytical TLC was con-
ducted on precoated silica gel plates (Merck 60F-254, 0.2 mm
thick). 1H and 13C NMR spectra were recorded on a Bruker AM 200
(4.5 T) spectrometer at 200.1 MHz and 50.3 MHz, respectively, and
autocalibrated to the deuterated solvent reference peak. IR spectra
were recorded as KBr disks on a Bruker Vector 22 FTIR system.
Electrospray ionization mass spectra were performed on a Bruker
ESQUIRE-LC spectrometer. Elemental analysis for C, H, and N
were performed by the CNRS Service Central d’Analyse (Vernai-
son, France).
Methyl 3,4-Dihydro-2-methyl-2H-1,2-benzothiazine-3-carbox-
ylate 1,1-Dioxide (5)
To a stirred solution of bromide derivative 4 (175 mg, 0.520 mmol)
in anhyd DMF (15 mL) under argon was added NaH (60% in min-
eral oil; 21 mg, 0.520 mmol). The mixture was heated at 80 °C for
14 h and then the solvent was evaporated. The residue was dissolved
in CH2Cl2 (20 mL), washed with H2O (20 mL), dried (MgSO4), and
the solvent evaporated. The residue was purified by column chro-
matography (silica gel; CH2Cl2) to afford the crude ester 5 (102 mg,
77%) as a white solid; mp 118–120 °C; Rf 0.18 (CH2Cl2–EtOH,
99:1).
2-Methyl-1,2-benzisothiazolin-3-one 1,1-Dioxide (1)6
Saccharin sodium salt hydrate and MeI were reacted according to
the known procedure to afford 1 as a white solid; mp 130–132 °C;
Rf 0.43 (CH2Cl2).
IR (KBr): 1745, 1334, 1176 cm–1.
2-(Hydroxymethyl)-N-methylbenzenesulfonamide (2)8
Derivative 1 and LiAlH4 were reacted according to the known pro-
cedure to afford 2 as a white solid; mp 76–78 °C; Rf 0.28 (CH2Cl2–
EtOH, 98:2).
1H NMR (CDCl3): d = 2.82 (s, 3 H, NCH3), 3.13 (dd, J = 5.6, 17.4
Hz, 1 H, CH2), 3.34 (dd, J = 11.7, 17.4 Hz, 1 H, CH2), 3.83 (s, 3 H,
OCH3), 4.75 (dd, J = 5.6, 11.7 Hz, 1 H, CH), 7.29–7.49 (m, 3 H,
ArH), 7.77 (d, J = 7.6 Hz, 1 H, ArH).
Methyl 2-[2-(Hydroxymethyl)-N-methylphenylsulfonamido]
Acetate (3)
To a stirred solution of amine 2 (1.50 g, 7.45 mmol) in anhyd DMF
(60 mL) under argon were added methyl bromoacetate (0.710 mL,
7.45 mmol) and NaH (60% in mineral oil; 298 mg, 7.45 mmol). The
mixture was heated at 50 °C for 3 h and then the solvent was evap-
13C NMR (CDCl3): d = 26.0, 30.0, 53.3, 59.8, 125.2, 128.3, 130.4,
132.8, 134.0, 135.7, 169.7.
Anal. Calcd for C11H13NO4S: C, 51.75; H, 5.13; N, 5.49. Found: C,
51.85; H, 5.38; N, 5.22.
Synthesis 2006, No. 4, 591–593 © Thieme Stuttgart · New York

SHORT PAPER
Methyl 3,4-Dihydro-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-Dioxide
593
Methyl 2-Methyl-2H-1,2-benzothiazine-3-carboxylate
1,1-Dioxide (6)
H, CH), 7.49–7.62 (m, 3 H, ArH), 7.73 (d, J = 7.4 Hz, 1 H, ArH),
8.43 (br s, 1 H, NH).
To a stirred solution of ester 5 (265 mg, 1.04 mmol) in CH2Cl2–CCl4
(1:5, 36 mL) were added NBS (203 mg, 1.14 mmol) and dibenzoyl
peroxide (50 mg, 0.206 mmol). The mixture was heated at reflux for
3 h in the darkness and then the solvent was evaporated. The residue
was purified by column chromatography (silica gel; CH2Cl2–EtOH,
99:1) to give the crude ester 6 (230 mg, 87%) as a pale yellow solid;
mp 134–136 °C; Rf 0.62 (CH2Cl2).
13C NMR (DMSO-d6): d = 23.6, 25.7, 35.1, 36.8, 53.1, 60.7, 64.3,
125.1, 128.7, 131.0, 133.5, 135.2, 135.8, 169.1.
EI-MS: m/z = 340 [M – I]+.
Anal. Calcd for C16H26IN3O3S·H2O: C, 39.59; H, 5.81; N, 8.66.
Found: C, 39.74; H, 5.66; N, 8.83.
IR (KBr): 1723, 1319, 1160 cm–1.
1H NMR (CDCl3): d = 3.26 (s, 3 H, NCH3), 3.93 (s, 3 H, OCH3),
7.51–7.67 (m, 4 H, ArH), 7.88 (dd, J = 4.0, 5.2 Hz, 1 H, ArH).
13C NMR (CDCl3): d = 36.7, 53.3, 122.9, 123.2, 129.7, 130.9,
131.4, 132.8, 133.8, 133.9, 163.2.
[3-(2-Methyl-1,1-dioxo-2H-1,2-benzothiazin-3-yl)carbonylami-
no]propyltrimethylammonium Iodide (10)
Yield: 79%; mp 250–252 °C; Rf 0.52 (CH2Cl2–MeOH–NH4OH,
50:46:4).
IR (KBr): 3500–3200, 1675, 1532, 1324, 1171 cm–1.
1H NMR (DMSO-d6): d = 1.99 (quin, J = 7.0 Hz,
2 H,
CH2CH2CH2), 2.47 (s, 3 H, NCH3), 2.96 (m, 2 H, NHCH2CH2CH2)
3.24 (t, J = 7.0 Hz, 2 H, NHCH2CH2CH2), 3.30 [s, 9 H, N+(CH3)3],
6.61 (s, 1 H, CH), 7.21–7.58 (m, 3 H, ArH), 7.88 (d, J = 7.2 Hz, 1
H, ArH), 8.05 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 22.2, 35.2, 38.4, 54.7, 64.1, 109.6,
126.7, 127.3, 128.3, 131.0, 131.1, 137.2, 141.0, 166.0.
Tertiary Amine Derivatives 7 and 8; General Procedure
To a stirred solution of the appropriate ester 5 (270 mg, 1.06 mmol)
or 6 (230 mg, 0.908 mmol) in xylene (15 mL) under argon was add-
ed 3-dimethylaminopropylamine (4 equiv). The mixture was heated
at 140 °C for 72 h (from 5) or 120 h (from 6) and then the solvent
was evaporated. The residue was purified by column chromatogra-
phy (silica gel; CH2Cl2–EtOH–NH4OH, 50:49:1) to afford the re-
spective amines 7 and 8 as colorless oils.
EI-MS: m/z = 338 [M – I]+.
Anal. Calcd for C16H24IN3O3S: C, 41.30; H, 5.20; N, 9.03. Found:
C, 41.02; H, 5.34; N, 8.86.
N-[3-(Dimethylamino)propyl]-3,4-dihydro-2-methyl-2H-1,2-
benzothiazine-3-carboxamide 1,1-Dioxide (7)
Yield: 67%; Rf 0.35 (CH2Cl2–EtOH–NH4OH, 50:48:2).
IR (KBr): 3400–3300, 1529, 1331, 1170 cm–1.
Acknowledgment
We thank ADIR, Servier (France) for financial support.
1H NMR (DMSO-d6): d = 1.58 (quin, J = 6.9 Hz,
2 H,
NHCH2CH2CH2), 2.14 [(s, 6 H, N(CH3)2], 2.26 (t, J = 6.9 Hz, 2 H,
NHCH2CH2CH2), 2.61 (s, 3 H, NCH3), 3.02–3.22 (m, 4 H, CH2CH,
NHCH2CH2CH2), 4.48 (dd, J = 6.4, 10.7 Hz, 1 H, CH), 7.43–7.60
(m, 3 H, ArH), 7.72 (d, J = 7.7 Hz, 1 H, ArH), 8.43 (br s, 1 H, NH).
13C NMR (DMSO-d6): d = 25.9, 27.2, 34.7, 38.4, 45.8, 57.7, 60.8,
125.0, 128.6, 130.9, 133.4, 135.3, 135.8, 168.5.
References
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Bizot-Espiard, J. G. International Patent PCT/FR01/04135,
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Med. Chem. submitted.
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N-[3-(Dimethylamino)propyl]-2-methyl-2H-1,2-benzothiazine-
3-carboxamide 1,1-Dioxide (8)
Yield: 51%; Rf 0.42 (CH2Cl2–EtOH–NH4OH, 50:48:2).
IR (KBr): 3400–3300, 1672, 1522, 1342, 1174 cm–1.
1H NMR (DMSO-d6): d = 1.90 (quin, J = 6.7 Hz,
2 H,
CH2CH2CH2), 2.72 [s, 6 H, N(CH3)2], 2.99–3.12 (m, 5 H, NCH3,
NHCH2CH2CH2), 3.32 (m, 2 H, NHCH2CH2CH2), 7.64–8.00 (m, 5
H, ArH), 8.82 (t, 1 H, J = 5.9 Hz, NH).
13C NMR (DMSO-d6): d = 25.0, 36.9, 37.4, 43.0, 55.4, 118.3,
123.1, 130.2, 131.4, 131.6, 132.6, 133.7, 138.5, 162.3.
QA Derivatives 9 and 10; General Procedure
To a stirred solution of the appropriate amine 7 (280 mg, 0.860
mmol) or 8 (250 mg, 0.773 mmol) in acetone (20 mL) under argon
was added excess MeI (20 equiv). The reaction mixture was stirred
at 70 °C for 1 h. The resulting precipitate was filtered, washed with
Et2O (20 mL) and acetone (20 mL), to afford the respective QA de-
rivatives 9 and 10 as white solids.
[3-(3,4-Dihydro-2-methyl-1,1-dioxo-2H-1,2-benzothiazin-3-
yl)carbonylamino]propyltrimethylammonium Iodide (9)
Yield: 83%; mp 249–251 °C; Rf 0.48 (CH2Cl2–MeOH–NH4OH,
50:46:4).
IR (KBr): 3500–3300, 1536, 1321, 1165 cm–1.
1H NMR (DMSO-d6): d = 1.89 (quin, J = 6.9 Hz,
2 H,
CH2CH2CH2), 2.62 (s, 3 H, NCH3), 3.04 [s, 9 H, N+(CH3)3], 3.10–
3.35 (m, 6 H, CH2CH, CH2CH2CH2), 4.57 (dd, J = 6.7, 10.2 Hz, 1
Synthesis 2006, No. 4, 591–593 © Thieme Stuttgart · New York