Synthesis of 2-(4-Methoxyphenyl)pyrrolo[2,1-d]pyrido[2,3-c]-[1,5]- thiazepin-3(2H)-one

Article abstract of DOI:10.3390/80900678

2-(4-Methoxyphenyl)pyrrolo[2,1-d]pyrido[2,3-c][1,5]thiazepin-3(2H)-one, a key intermediate in the synthesis of pyrrolopyridothiazepine derivatives, was synthesized from bis(4H-pyrrolo-3-pyridyl)disulfide and α-bromo-(4- methoxy-phenyl)acetic acid ethyl ester in order to develop a novel calcium channel antagonist.

Full text of DOI:10.3390/80900678

Molecules 2003, 8, 678-686
molecules
ISSN 1420-3049
http://www.mdpi.org/
Synthesis of 2-(4-Methoxyphenyl)pyrrolo[2,1-d]pyrido[2,3-c]-
[1,5]-thiazepin-3(2H)-one
Eunsook Ma
College of Pharmacy, Catholic University of Daegu, Hayang, 712-702, Korea, Tel. (+82)-053-850-
3621; Fax. (+82)-053-850-3602.
* Author to whom correspondence should be addressed; E-mail: masook@cataegu.ac.kr
Received: 7 March 2003; in revised form 24 July 2003/ Accepted: 3 August 2003 / Published: 15
August 2003
Abstract: 2-(4-Methoxyphenyl)pyrrolo[2,1-d]pyrido[2,3-c][1,5]thiazepin-3(2H)-
one, a key intermediate in the synthesis of pyrrolopyridothiazepine derivatives, was
synthesized from bis(4H-pyrrolo-3-pyridyl)disulfide and α-bromo-(4-methoxy-
phenyl)acetic acid ethyl ester in order to develop a novel calcium channel antagonist.
Keywords: Calcium channel antagonist, Thiation, Pyrrolopyridothiazepine,
Intramolecular cyclization
Introduction
Calcium channel antagonists (calcium entry blockers) are known to be clinically useful agents in
treating hypertension, angina pectoris, and certain cardiac arrythmias. Structurally they are classified
into three groups: 1,4-dihydropyridines (nifedipine, nitrendipine), phenylalkylamines (verapamil) and
benzothiazepines (diltiazem) (Figure 1) [1]. Their major pharmacological effects appear to be exerted

Molecules 2003, 8
679
by selectively inhibiting the influx of extracellular Ca2+ through L-type voltage-dependent calcium
channels and subsequently inhibiting the myocardial contraction and having the vasodilator effects as
a result [2,3]. A considerable number of structure-activity relationship studies of 1,4-dihydropyridine
series have been delineated [4,5], however, compared to the 1,4-dihydropyridine series, there has been
limited information available on structure-activity relationships in the diltiazem series [6]. Although
diltiazem is widely used in therapy, it has a relatively short duration of action and is known to cause
significant prolongation of cardiac P-R intervals [7].
The 8-chloro derivative (benzothiazepinone numbering) TA 3090 (Figure 1), a second generation
diltiazem analogue, has recently been introduced into clinical use [8,9]. This compound is a more
potent antihypertensive than diltiazem in animals. The combination of proven clinical utility, the need
for improvements in potency and duration of action, and limited structure-activity data made the study
of diltiazem and related compounds an attractive area for further research [10,11].
Figure 1. Representative Ca2+ channel antagonists and compound 1.
OMe
OMe
NO2
OMe
MeOOC
Me
COOR
OMe
NC
CH(Me)2
N
Me
N
Me
R=Me: Nifedipine
=Et : Nitrendipine
Verapamil
OMe
OMe
S
X
H
S
OCOMe
N
H
O
N
O
N
N
Me
Me
X= H : Diltiazem
X=Cl : TA 3090
1

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680
In the present paper an approach for designing a pyrrolopyridothiazepine derivative as a novel
calcium channel antagonist is described. The plan was to use 4-aminopyridine as the starting material
instead of the 4-chloroaniline part of TA 3080. Also, the replacement of the amide linkage of
diltiazem with a bioisosteric pyrrole ring was attempted to improve the short duration of action, and
the sulfur group was maintained for the activity. 2-(4-Methoxyphenyl)pyrrolo[2,1-d]pyrido[2,3-
c][1,5]thiazepine-3(2H)-one (1) was prepared as a key intermediate of this pyrrolopyridothiazepine
series.
Results and Discussion
The preparation of compound 1 was accomplished by the reaction sequence shown in Scheme 1.
Because the sulfur group is known to act as an important pharmacophore exhibiting antihypertensive
activity, we tried to replace the 3-hydrogen of 4-aminopyridine with a SH group. The literature
contains various examples of the synthesis of thiols by the direct thiation of organomagnesium or
organolithium reagents with elemental sulfur [12,13], but this type of reaction has been of limited
utility, since clean products are usually not obtained, and sulfides are formed as significant by-
products. 4-Aminopyridine was reacted with pivaloyl chloride at 0ûC in the presence of triethylamine
to form 4-pivaloylaminopyridine (2) in high yield. The pivaloyl group is a powerful auxiliary for
direct lithiation [14]. Double lithiation of 4-pivaloylaminopyridine using 2.5 M n-butyllithium
produced a white precipitate of the dilithio derivative. Reaction of this species with the electrophile
tetraisopropylthiuram disulfide (TITD) produced 3-(N,N-diisopropyldithiocarbamato)pyridine (3)
in good yield (87 %). TITD was directly synthesized from isopropylamine, carbon disulfide, and
potassium ferricyanide at 0ûC [15]. Attempted removal of the pivaloyl group using 5 M-HCl solution
produced a 2-tert-butylthiazolo[5,4-c]pyridine (4) in 99 % yield as shown in Scheme 1 [16]. The
subsequent alkaline hydrolysis of compound 4 produced the disulfide 5. Compound 6 was prepared
by reaction of 2,5-dimethoxytetrahydrofuran with bis(2-amino-4-pyridyl)disulfide (5). Bis(4H-
pyrrolo-3-pyridyl)disulfide(6) was reduced with NaBH4 in refluxing ethanol to give 3-mercapto-4H-
pyrrolopyridine and the latter subsequently reacted with α-bromo-4-methoxyphenylacetic acid ethyl
ester (7) to give compound 8. Compound 7 was obtained from 4-methoxyphenylacetic acid by an
esterification reaction with absolute ethanol containing a catalytic amount of concentrated H2SO4, and
then bromination with N-bromosuccinimide. Hydrolysis of ester 8 with 5 % NaOH solution afforded
4-methoxy-α-[(4H-pyrrolo-3-pyridyl)thio]phenyl acetic acid (9). Intramolecular cyclization of the
acid 9 using phosphorus pentachloride gave the target compound 1. All synthesized compounds were
identified with IR, NMR, and mass spectra, respectively.

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681
Scheme 1.
S
S C N(iPr)2
a
b
N
N
N
CH3
CH3
NH
C CH3
NH
C
C C CH3
NH2
CH3
O
O CH3
3
2
c
S S
N
N
S
S
e
CH3
C CH3
CH3
S
d
N
N
N
N
N
N
NH2 H2N
5
4
6
f
OCH3
OCH3
OCH3
S
h
g
S
N
S
O
N
N
COOH
COOC2H5
N
N
N
1
9
8
Reagents and conditions : (a) Pivaloyl chloride, triethylamine, anhydrous CH2Cl2, 0ûC;
(b) TITD, 2.5 M n-butyllithium, -78ûC, anhydrous THF; (c) 5 M-HCl, reflux; (d) 5 M
NaOH, solid NaOH, reflux; (e) 2,5-Dimethoxytetrahydrofuran, glacial acetic acid, 110ûC;
(f) i) NaBH4, absolute ethanol, reflux, ii) α-bromo-4-methoxyphenyl acetic acid ethyl
ester (7), ethanol, rt; (g) 5 % NaOH, methanol/THF (1:1), rt; (h) PCl5, anhydrous CH2Cl2,
rt , 60ûC.
Acknowlegments
The author wishes to thank the Catholic University of Daegu for financial support.

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682
Experimental
General
Reactions were performed under an atmosphere of nitrogen. Solvents were purified and dried
prior to use. Anhydrous MgSO4 was used for drying reaction mixtures. Melting points were measured
on a Thomas-Hoover melting point apparatus in open capillary tubes and are not corrected. 1H-NMR
spectra were obtained on a Gemini 200 MHz spectrometer in CDCl3 or D2O. Chemical shifts (δ) are
reported in ppm relative to tetramethylsilane and coupling constants (J) in Hz. IR spectra were
determined on a Jasco FT-IR 300E spectrometer as KBr pellet. GC-mass spectra were recorded on a
Shimadzu GC-QP 5000 spectrometer. Analytical TLC was performed on Merck precoated silica
gel 60 F254 plates. Column chromatography was carried out on Merck silica gel (9385, 230-400
mesh).
4-(Pivaloylamino)pyridine (2).
A solution of pivaloyl chloride (24.63 mL, 0.2 mol) in anhydrous CH2Cl2 (36 mL) was cautiously
added at 0ûC to a solution of 4-aminopyridine (18.82 g, 0.2 mol) and triethylamine (27 mL) in
anhydrous CH2Cl2 (90 mL). The reaction mixture was stirred in an ice bath for 1 hour and then
allowed to warm to room temperature and stirred overnight. Cold water (100 mL) was added and the
CH2Cl2 layer was separated from the aqueous one. The organic phase was washed with saturated
NaHCO3 solution (2×40 mL) and water, dried over anhydrous MgSO4, filtered and concentrated to
yield a crude brown product that was recrystallized from ethyl acetate/n-hexane (1:5) to yield the pure
product as white needles, yield: 30.41 g (85 %); mp: 135-137 ûC; IR (KBr) cm-1: 3507, 2967, 1701,
1
1591; H-NMR (CDCl3) δ: 1.33 (9H, s, -C(CH3)3), 7.51 (2H, d, J=6.1Hz, ArH), 7.61 (1H, br s, NH),
8.48 (2H, d, J=5.8Hz, ArH).
3-(N,N-Diisopropyldithiocarbamato)-4-(pivaloylamino)pyridine (3).
A solution of 4-(pivaloylamino)pyridine (2, 17.82 g, 0.1 mol) in dry tetrahydrofuran (160 mL)
was cooled to -78℃ under N2 gas and 2.5 M n-butyllithium (84 mL, 0.21 mol) was slowly added.
The reaction mixture was stirred for 4 hours at 0ûC and recooled to -78ûC. A solution of
tetraisopropylthiuram disulfide (TITD, 35.26 g, 0.1 mol) in dry tetrahydrofuran (140 mL) was slowly
added. After completion of the addition, the cooling bath was removed. After stirring for 2 hours,
water (180 mL) was carefully added, followed by diethyl ether (3×180 mL). The combined organic
solutions were washed with brine and dried over anhydrous MgSO4. Rotary evaporation of the solvent
gave the crude product, which was recrystallized from ethyl acetate to provide pure white product

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(25.22 g, 71 %). Evaporation of the mother liquors gave a brown oil, which when purified by column
chromatography (ethyl acetate/n-hexane=1:5) gave an additional 5.4 g (15 %) of product. Total yield:
1
30.62 g (87 %); mp: 117-119℃; IR (KBr) cm-1: 3450, 2965, 1686, 1591; H-NMR (CDCl3) δ: 1.25
(9H, s, -C(CH3) 3), 1.53 (12H, br s, -CH(CH3) 2×2), 4.80 (2H, very br s, -CH×2), 8.37 (1H, d,
J=5.5Hz, ArH), 8.50 (1H, s, ArH), 8.60 (1H, d, J=5.5Hz, ArH).
2-t-Butylthiazolo[5,4-c]pyridine (4).
A mixture of 2-(N,N-diisopropyldithiocarbamato)-4-(pivaloylamino)pyridine (3, 16 g, 45.25
mmol) and 5 M HCl solution (155 mL) was refluxed for 5 hours. The mixture was allowed to reach
room temperature, and the acidic solution was then washed with ethyl ether (70 mL) and then
neutralized with 20 % NaOH solution in an ice bath. The aqueous layer was extracted with CH2Cl2
(3×100 mL), followed by drying over anhydrous MgSO4. The organic solvent was evaporated leaving
a solid that was purified by recrystallization from diethyl ether/n-hexane (1:3) to yield a white
1
amorphous solid; yield: 8.63 g (99 %); mp: 52-54ûC; IR (KBr) cm-1: 2960, 1580, 1510, 1440; H-
NMR (CDCl3) δ: 1.60 (9H, s, -C(CH3) 3), 8.29 (1H, d, J=6.7Hz, ArH), 8.73 (1H, d, J=6.4Hz, ArH),
10.04 (1H, s, ArH).
Bis(4-amino-3-pyridyl)disulfide (5)
A mixture of 2-tert-butylthiazolo[5,4-c]pyridine (4, 5 g, 26 mmol) and 10 % aqueous NaOH (80
mL) was heated under reflux for 6 hours. After this time, if the starting material was still visible as an
oil on the surface, the mixture was allowed to cool down and some NaOH pellets (8 g) were added
and the mixture refluxed for another 6 hours. The reaction mixture was cooled down, washed with
dichloromethane and the aqueous layer was neutralized with concentrated HCl. It was then
continuously extracted with ethyl acetate for 48 hours and evaporated to yield a yellow solid (2.53 g).
Evaporation of the solvent after several extractions yielded further disulfide (1.05 g). Yield: 3.58 g
1
(55 %); mp: 136-138℃; IR (KBr) cm-1: 3389, 1634, 1536; H-NMR (CDCl3) δ: 6.55(2H, brs, NH2),
6.71 (2H, d, J=5.8Hz, ArH), 7.70 (1H, s, ArH); MS (m/z): 250 (M+).
Bis(4H-pyrrolo-3-pyridyl)disufide (6)
To a solution of bis(4-amino-3-pyridyl) disulfide (5, 1 g, 4 mmol) in glacial acetic acid (15 mL),
2,5-dimethoxytetrahydrofuran (1.04 g, 7.83 mol) in glacial acetic acid (5 mL) was slowly added and
the mixture heated at 110ûC for 1 hour. Evaporation of the acetic acid provided a dark brown oily
product which was extracted with diethyl ether (3×30 mL) and washed successively with saturated
NaHCO3 and water and then dried over anhydrous MgSO4. After filtering the filtrate was concentrated

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684
to give the crude product, which was purified by column chromatography (ethyl acetate/n-
hexane=1:1) to provide a pale yellow solid, yield: 630 mg (31 %); mp: 115.3-116.8ûC; IR (KBr) cm-1:
1648, 1568; 1H-NMR (CDCl3) δ: 6.35 (2H, t, pyrrole-H), 6.89 (2H, t, pyrrole-H), 7.16(1H, d, J=5.3Hz,
ArH), 8.53 (1H, d, J=5.2Hz, ArH), 8.67 (1H, s, ArH); MS(m/z): 175 (M+/2).
4-Methoxy-α-[(4H-pyrrolo-3-pyridyl)thio]phenyl acetic acid ethyl ester (8)
A solution of bis(4H-pyrrolo-3-pyridyl)disulfide (6, 600 mg, 1.7 mmol) in 60 mL of absolute
ethanol was heated to reflux. Sodium borohydride (132 mg, 3.4 mmol) was slowly added over 10
minutes. After completion of the addition the mixture was allowed to cool down, α-bromo-4-
methoxyphenyl acetic acid ethyl ester 7 (936 mg, 3.4 mmol) was added and the resulting mixture was
stirred for 5 hours at room temperature. The reaction mixture was concentrated to half its volume,
water was added, and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined
organic layers were dried and evaporated to give the crude product, which was purified by column
chromatography (ethyl acetate/n-hexane=1:3) to afford the title compound, Yield: 507 mg (81 %);
mp: 165.6-166.8ûC; IR (KBr) cm-1: 1725; 1H-NMR (CDCl3) δ: 1.09 (3H, t, CH3), 3.77 (3H, s, OCH3),
3.97-4.28 (2H, m, CH2), 4.28 (1H, s, CH) 6.41 (2H, t, pyrrole-H), 6.78 (2H, t, pyrrole-H), 7.13-7.21
(5H, m, ArH), 8.53 (1H, d, J=5.2Hz, ArH), 8.69(1H, s, ArH); MS(m/z): 368(M+).
4-Methoxy-α-[(4H-pyrrolo-3-pyridyl)thio]phenyl acetic acid (9)
The ester 8, (500 mg, 1.36 mmol) was dissolved in a 1:1 ethanol and tetrahydrofuran mixture (50
mL), and 5 % aqueous NaOH (100 mL) was slowly added. The reaction mixture was then stirred at
room temperature for 1 hour, concentrated, and acidified to pH 3∼4 with dilute HCl. The brown oil
was extracted with CH2Cl2, and the organic phase was diluted, filtered, and concentrated to give the
crude acid. Recrystallization from methanol and n-hexane (1:4) gave the purified white solid, yield:
380 mg (82 %); mp :216-218 ûC; IR (KBr) cm-1: 3410, 1720; 1H-NMR (D2O) δ: 3.72 (3H, s, OCH3),
4.91 (1H, s, CH), 6.34 (2H, t, pyrrole-H), 6.85 (2H, t, pyrrole-H), 7.16-7.23 (4H, m, ArH), 7.35 (1H, d,
ArH), 8.48 (1H, d, J=7.2Hz, ArH), 8.63 (1H, s, ArH); MS(m/z): 340(M+).
2-(4-Methoxyphenyl)pyrrolo[2,1-d]pyrido[2,3-c][1,5]thiazepine-3(2H)-one (1)
A suspension of PCl5 (276 mg, 1.32 mmol) in CH2Cl2 (20 mL) was carefully added to a well-
stirred solution of compound 9 (300 mg, 0.88 mmol) in anhydrous CH2Cl2 (40 mL). The mixture was
heated at 60ûC for 12 hours and then further reacted at the room temperature for 12 hours. The solvent
was removed under reduced pressure and the dark oily residue was treated with ethyl acetate. The
organic layer was washed with 5% aqueous NaOH and water, then dried, filtered and concentrated to

Molecules 2003, 8
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give a brown pasty residue which was purified by column chromatography (ethyl acetate/n-
1
hexane=1:3). Yield: 200 mg (72%); mp: 145-147ûC; IR (KBr) cm-1: 1650; H-NMR (CDCl3) δ: 3.76
(3H, s, OCH3), 4.30 (1H, s, CH), 6.41 (1H, t, pyrrole-H), 6.76 (2H, d, J=8.4Hz, pyrrole-H),
7.12∼7.21 (5H, m, ArH), 8.50 (1H, d, J=7.2Hz, ArH), 8.68 (1H, s, ArH); MS(m/z): 322(M+).
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Sample Availability: Samples of compounds 1, 2, 3, 4, 8 and 9 are available from the author.
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