Synthesis of n-methyl-3-carboxy-2-chloro-dibenzo[c,f][1,4,5]oxa-thiazepine s,s-dioxide and its derivatives

Article abstract of DOI:10.1007/s10593-010-0438-9

A new dibenzo-condensed oxathiazepinecarboxylic acid was obtained starting from the methyl ester of 2,4-dichloro-5-chlorosulfonylbenzoic acid. Derivatives were obtained from N-phenylamide and N-methylamide of 2,4-dichloro-5- chlorosulfonylbenzoic acid. Methods for the preparation of the starting aromatic sulfonyl chlorides were proposed.

Full text of DOI:10.1007/s10593-010-0438-9

Chemistry of Heterocyclic Compounds, Vol. 45, No. 11, 2009
SYNTHESIS OF N-METHYL-
3-CARBOXY-2-CHLORO-
DIBENZO[c,f][1,4,5]OXA-
THIAZEPINE S,S-DIOXIDE
AND ITS DERIVATIVES
A. S. Bychenkov1*, A. V. Tarasov1, P. K. Pisarev1,
V. Sh. Feldblum1, and Yu. A. Moskvichev1
A new dibenzo-condensed oxathiazepinecarboxylic acid was obtained starting from the methyl ester of
2,4-dichloro-5-chlorosulfonylbenzoic acid. Derivatives were obtained from N-phenylamide and
N-methylamide of 2,4-dichloro-5-chlorosulfonylbenzoic acid. Methods for the preparation of the
starting aromatic sulfonyl chlorides were proposed.
Keywords: dibenzoxathiazepinecarboxylic acid, diacid chloride of 2,4-dichloro-5-sulfobenzoic acid,
methyl ester, N-phenylamide and N-methylamide of 2,4-dichloro-5-chlorosulfonylbenzoic acid.
In a continuous of previous work [1-3] on the synthesis of sulfonylamides of dibenzo-condensed
seven-membered heterocyclic compounds, we have developed a method for the preparation of aromatic
carboxylic acid 1, which contains a sulfonyl group in a seven-membered ring. This compound is an interesting
candidate for pharmaceutical purposes since a compound with a similar structure, namely, the tricyclic
antidepressant tianeptine 2, is commonly used in medical practice [2].
O
O
Me
O
Me
O
S
N
S
N
HOOC
Cl
O
Cl
(CH2)6 NH
HOOC
1
2
Aromatic carboxylic acid 1 may be synthesized from sulfonylamide 3, but the latter could not be
obtained by the reaction of sulfonyl chloride 4 with N-methyl-2-aminophenol 5 due to tar formation.
_______
* To whom correspondence should be addressed, e-mail: bychenkov@ystu.ru.
1Yaroslavl State Technical University, 150023 Yaroslavl, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1728-1733, November, 2009.
Original article submitted June 7, 2008, submitted after revision March 3, 2009.
0009-3122/09/4511-1391©2009 Springer Science+Business Media, Inc.
1391

Me
HN
HOOC
Cl
O
S
Me
N
SO2Cl
Cl
HOOC
Cl
i
+
–HCl
HO
O
5
4
Cl
HO
3
i: MeCN, 40°C, 40 min
The use of carboxyl group derivative 6 instead of sulfonyl chloride 4 considerably facilitates the
preparation of the corresponding sulfonylamides. Thus, the reaction of aminophenol 5 with the methyl ester 6a,
N-phenylamide 6b, and N-methylamide of 2,4-dichloro-5-chlorosulfonylbenzoic acid 6c at 40°C over 40 min in
acetonitrile as solvent gave in yields over 85% the corresponding sulfonylamides 7, which convert to
dibenzoxathiazepines 8 upon heating at 70°C in DMF in the presence of K2CO3 over 10 min practically in
quantative yields.
O
Me
O
ROC
Cl
S
N
O
S
Me
N
SO2Cl
Cl
ROC
Cl
ii
ROC
i
5
+
–KHCO ,
–KCl
O
3
–HCl
Cl
O
6a–c
8a–c
HO
Cl
7a–c
i: MeCN, 40°C, 40 min; ii: DMF, K2CO3, 70°C, 10 min;
6–8 a R = OMe, b R = NHPh, c R = NHMe
The alkaline hydrolysis of the ester group in 8a leads to the preparation of the desired aromatic
carboxylic acid 1.
Me
O
O
S
N
i
1
MeOOC
–MeOH
O
Cl
8a
i: 1. KOH, H2O, reflux; 2. H+
The presence of a carboxyl group and chlorine atom opens pathways for further functionalization of the
product obtained.
The synthesis of the starting sulfonyl chlorides 6a,b is based on the significant difference in the
reactivity of the chloroformyl and sulfonyl chloride groups of the dichloride of the 3-sulfobenzoic acid in its
reactions with methanol [5] and aniline [6, 7].
SO2Cl
Cl
PhHNOC
Cl
SO2Cl
Cl
SO2Cl
Cl
ClOC
Cl
MeOOC
Cl
ii
i
–HCl
–HCl
9
6b
6a
i: MeCN, MeOH, NEt3, 20°C, 1 h; ii: MeCN, PhNH2, 20°C, 1 h
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We were unable to carry out a regioselective reaction of dichloride 9 with an aliphatic amine. Analysis
of the reaction mixture showed replacement at both functional groups in addition to a side-product [7]. Thus, we
developed a synthesis for sulfonyl chloride 6c based on the prior sulfochlorination of 2,4-dichlorobenzoic
acid 10 with subsequent amidation of the carboxyl group of the N-methylsulfaminic acid without isolation of the
intermediate 2,4-dichloro-5-chlorosulfonylbenzoic acid [8].
SO2Cl
Cl
HOOC
Cl
MeHNOC
i
Cl
Cl
6c
10
i: 1) HClSO3, 140°C, 2 h; 2) 110°C, MeHNSO3H, 2 h
Under these conditions, the desired chlorosulfonylbenzamide 6c was obtained in 89% yield. The
substitution of the N-methylsulfaminic acid with the corresponding urea derivative CO(NHMe)2 permitted us to
increase the yield of the final product 6c to 95% with lowering of the amidation reaction temperature to 90°C.
It proved impossible to obtain products 6a-c used in the synthesis of both dibenzoxa-
thiazepinecarboxylic acid 1 and derivatives of this acid 8a-c by the direct sulfochlorination of the corresponding
derivatives of 2,4-dichlorobenzoic acid due to the polyvariant opening of the sulfo group to give benzanilides or
the chemical instability of the ester and amide groups under the conditions of this reaction.
EXPERIMENTAL
1
The H NMR spectra were taken on a Bruker DRX 500 spectrometer at 500 MHz in DMSO-d6 with
TMS as the internal standard. The nitrogen, carbon, and hydrogen contents were determined on a FLASH 1112
elemental analyzer, while the sulfur content was determined titrimetrically by combustion in a Shöniger flask.
Commercial samples of 2,4-dichlorobenzoic acid 10 and N-methyl-2-aminophenol were used [9].
Sulfonyl chloride 4 and dichloride 9 were synthesized analogously to the sulfonyl chlorides of benzoic
acid and the dichloride derivatives of 3-sulfobenzoic acid. The general methods for these procedures were given
by Pisarev [8] and Timoshenko [6], respectively.
The methyl ester 6a [5], N-phenylamide 6b [6], and N-methylamide of 2,4-dichloro-5-chloro-
sulfonylbenzoic acid 6c [8] were obtained by procedures given in our previous work.
Methyl ester of 2,4-dichloro-5-chlorosulfonylbenzoic Acid (6a) was obtained in 72% yield;
mp 59-61°C. Found, %: C 32.25; H 1.64; Cl 33.88; S 10.78. C8H5Cl3O4S. Calculated, %: C 31.65; H 1.66;
Cl 35.04; S 10.56.
N-Phenylamide of 2,4-dichloro-5-chlorosulfonylbenzoic Acid (6b) was obtained in 80% yield;
mp 143-145°C. Found, %: C 42.80; H 2.10; Cl 29.11; N 3.75; S 8.77. C13H8Cl3NO3S. Calculated, %: C 42.82;
H 2.21; Cl 29.17; N 3.84; S 8.79.
N-Methylamide of 2,4-dichloro-5-chlorosulfonylbenzoic Acid (6c) was obtained in 95% yield;
mp 167-168°C. Found, %: C 31.68; H 1.91; Cl 35.14; N 4.65; S 10.54. C8H6Cl3O3S. Calculated, %: C 31.76;
H 2.00; Cl 35.15; N 4.63; S 10.60.
Synthesis of sulfonylamides 7a-c (General Method). A sample of the corresponding sulfonyl
chloride 6a-c (4 mmol) was added with stirring to a solution of N-methyl-2-aminophenol 5 (8 mmol) in
acetonitrile (2 ml) in a three-necked flask equipped with a stirrer and thermometer. The reaction mixture was
heated at 40°C for 40 min, cooled to room temperature, and poured into water (30 ml). The precipitate formed
was filtered off, recrystallized from 2-propanol–DMF 1:2, and dried in a desiccator to constant weight.
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Methyl ester of 2,4-dichloro-5-[(2-hydroxyphenyl)methylsulfamoyl]benzoic acid (7a) was obtained
in 88% yield; mp 146-147°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.25 (3H, s, SO2NCH3); 3.57 (3H, s, CO2CH3);
6.75-6.81 (2H, m, H-4', H-6'); 7.09 (1H, dd, J = 7.9, J = 1.3, H-3'); 7.15 (1H, t.d, J = 8.9, J = 1.4, H-5'); 8.05
(1H, s, H-3); 8.15 (1H, s, H-6); 9.73 (1H, s, OH). Found, %: C 46.36; H 3.30; N 3.73; S 8.00. C15H13Cl2NO5S.
Calculated, %: C 46.17; H 3.36; N 3.59; S 8.22.
N-Phenyl-2,4-dichloro-5-[(2-hydroxyphenyl)methylsulfamoyl]benzamide (7b) was obtained in 91%
yield; mp 197-200°C. 1H NMR spectrum, δ, ppm (J, Hz): 3.26 (3H, s, SO2NCH3); 6.76 (1H, td, J = 7.7, J = 1.3,
H-5'); 6.84 (1H, dd, J = 8.2, J = 1.3, H-3'); 7.08-7.17 (3H, m, H-2", H-3", H-4"); 7.36 (2H, t, J = 8.1, H-1",
H-5"); 7.66 (2H, d, J = 7.7, H-6'); 7.90 (1H, s, H-3); 8.01 (1H, s, H-6); 9.57 (1H, s, OH); 10.52 (1H, s, CONH).
Found, %: C 52.83; H 3.53; N 6.53; S 7.00. C20H16Cl2N2O4S. Calculated, %: C 53.23; H 3.57; N 6.21; 7.10.
N-Methyl-2,4-dichloro-5-[(2-hydroxyphenyl)methylsulfamoyl]benzamide (7c) was obtained in
1
89% yield; mp 207-208.5°C. H NMR spectrum, δ, ppm (J, Hz): 2.74 (3H, d, J = 4.6, COHNCH3); 3.25 (3H, s,
SO2NCH3); 6.75 (1H, td, J = 7.7, J = 1.4, H-5'); 6.82 (1H, d, J = 8.2, J = 1.3, H-6'); 7.06 (1H, dd, J = 7.9,
J = 1.6, H-3'); 7.14 (1H, td, J = 8.1, J = 1.7, H-4'); 7.59 (1H, s, H-3); 7.91 (1H, s, H-6); 8.5 (1H, br. s, CONH);
9.56 (1H, s, OH). Found, %: C 46.58; H 3.66; N 7.38; S 8.11. C15H14Cl2N2O4S. Calculated, %: C 46.28; H 3.63;
N 7.20; S 8.24.
An attempt to synthesize sulfonylamide 3 was carried out analogously to the procedure for preparation
of sulfonylamides 7a-c.
Synthesis of dibenzoxathiazepines 8a-c (General Method). A solution of
corresponding
sulfonylamide 7a-c (3 mmol) in DMF (10 ml) and potassium carbonate (6 ml) was heated with stirring at 70°C
for 10 min, then cooled to room temperature, and poured into (10 ml) water. The precipitate formed was
recrystallized from 2-propanol–DMF, 1:1, and dried in a desiccator to constant weight.
N-Methyl-2-chloro-3-methoxycarbonyldibenzo[c,f][1,4,5]oxathiazepine S,S-Dioxide (8a) was
1
obtained in 92% yield; mp 165-166°C. H NMR spectrum, δ, ppm (J, Hz): 3.3 (3H, s, SO2NCH3); 3.89 (3H, s,
CO2CH3); 7.38 (1H, td, J = 7.6, J = 1.7, H-8); 7.44-7.51 (2H, m, H-7, H-9); 7.55 (1H, dd, J = 7.8, J = 1.6,
H-10); 7.85 (1H, s, H-1); 8.5 (1H, s, H-4). Found, %: C 51.03; H 3.43; N 4.11; S 8.63. C15H12ClNO5S.
Calculated, %: C 50.93; H 3.42; N 3.96; S 9.06.
N-Methyl-2-chloro-3-phenylcarbamoyldibenzo[c,f][1,4,5]oxathiazepine S,S-Dioxide (8b) was obtained
1
in 94% yield; mp 176-178°C. H NMR spectrum, δ, ppm (J, Hz): 3.26 (3H, s, SO2NCH3); 7.13 (1H, t, J = 7.4,
H-8); 7.34-7.40, 7.45-7.52, 7.56 (6H, m, H-11, H-12, m, H-13, H-14, H-15, dd, J = 1.5, J = 7.9, H-10); 7.68
(2H, d, J = 7.9, H-7, H-9); 7.85 (1H, s, H-1), 8.0 (1H, s, H-4); 10.52 (1H, s, CONH). Found, %: C 58.10;
H 3.69; N 6.77; S 7.48. C20H15ClN2O4S. Calculated, %: C 57.90; H 3.64; N 6.75; S 7.73.
N-Methyl-2-chloro-3-methylcarbamoyldibenzo[c,f][1,4,5]oxathiazepine S,S-Dioxide (8c) was obtained
in 91% yield; mp 201-203°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.77 (1H, d, J = 4.6, CONHCH3); 3.30 (3H, s,
SO2NCH3); 7.35 (1H, td, J = 7.5, J = 1.7, H-8); 7.43-7.50 (2H, m, H-7, H-9); 7.54 (1H, dd, J = 7.9, J = 1.6,
H-10); 7.76 (1H, s, H-1); 7.80 (1H, s, H-4); 8.51 (1H, s, CONH). Found, %: C 51.45; H 3.75; N 8.14; S 8.94.
C15H13ClN2O4S. Calculated, %: C 51.07; H 3.71; N 7.94; S 9.09.
N-Methyl-3-carboxy-2-chlorodibenzo[c,f][1,4,5]oxathiazepine S,S-dioxide (1).
A mixture of
aromatic carboxylic acid methyl ester 8a (2 mmol), KOH (4 mmol), and water (10 ml) was heated at reflux until
the solid residue dissolved, cooled to room temperature, and filtered to remove the mechanical impurities. The
filtrate was made acidic by adding 10% hydrochloric acid. The precipitate formed was filtered off and dried in a
desiccator to constant weight. The yield of acid 1 was 95%; mp 213-215°C. 1H NMR spectrum, δ, ppm (J, Hz):
3.22 (3H, s, SO2NCH3); 7.38 (1H, td, J = 8.4, J = 1.4, H-8); 7.44-7.51 (2H, m, H-7, H-9); 7.55 (1H, dd, J = 8.1,
J = 0.8, H-10); 7.8 (1H, s, H-1); 8.21 (1H, s, H-4); 13.8 (1H, br. s, CO2H). Found, %: C 49.01; H 2.86; N 4.03;
S 9.21. C14H10ClNO5S. Calculated, %: C 49.49; H 2.97; N 4.12; S 9.44.
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