Convenient synthesis of novel pyrimido[4,5-b][1,5]benzothiazepines

Article abstract of DOI:10.1002/jhet.4141

Reaction of 4,6-dichloropyrimidine-5-carbaldehyde with amines in chloroform gave 4-(substitutedamino)-6-chloro-pyrimidine-5-carbaldehydes derivatives at low temperature. Treatment of the latter products with 2-aminobenzenethiol in alkaline benzene and the

Full text of DOI:10.1002/jhet.4141

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Convenient Synthesis of Novel Pyrimido[4, 5- b][1,
5]benzothiazepines
Mohsen Nikpour*, Neda Hassanzadeh
Abstract: Reaction of 4,6-Dichloropyrimidine-5-carbaldehyde with
amines in chloroform gave 4-(substitutedamino)-6-chloro-pyrimidine-
5-carbaldehydes derivatives at low temperature. Treatment of the
latter products with 2-aminobenzenethiol in alkaline benzene and
then in boiling acetonitrile gave a novel group of 11H-pyrimido[4,5-
b][1, 5]benzodiazepine derivatives. Structures of the products
confirmed by 1HNMR, IR and Mass spetra.
number 4 position of two 4,6-dichloropyrimidine-5-carbaldehyde
1 molecules to give a polymeric product as shown in Scheme 1.
For fixing of this problem, it was decided to substitute a chlorine
atom of 4,6-dichloropyrimidine-5-carbaldehyde 1 by amines. So
4,6-dichloropyrimidine-5-carbaldehyde 1 reacted with amines
according to an earlier report55 as shown in Scheme 1 and the
strategy
b][1,5]benzothiazepines 5a-i based on the condensation of 2-
aminobenzenethiol with 4-(substitutedamino)-6-chloro-
pyrimidine-5-carbaldehydes 2a-i.
for
the
synthesis
of
pyrimido[4,5-
3
Introduction
The growing pharmaceutical and agrochemical interest for fused
pyrimidines has focused the attention of researchers to search
for efficient and general routes to these molecules in
synthetically useful yields. Among the privileged heterocyclic
scaffolds,
[1,5]benzothiazepines
and
fused
[1,5]benzothiazepines were on the scope of chemists efforts for
several years1,2. These compounds have been described as
Calcium channel blockers3-6, hypotensive7-10, drugs of liver
diseases11,12, antidepressants13-15, anticholinesterase inhibitors16-
17, anticancer18-23, diuretics 24, antimicrobials25-38, anti HIV39-41
and anti tuberculosis42,43 agents. The useful procedures for the
preparation of 1,5-benzothiazepines are mainly based on the
condensation of 2-aminobenzenethiol with α, β- unsaturated
ketones2. These findings encouraged scientists to prepare
pyrimido[4,5-b][1,4]benzothiazepines by a) condensation of 5-
aminopyrimidine-4-thiol with 2-chlromethylbenzoates44 and b) 4-
chloropyrimidin-5-amine on the Bischler−Napieralski-type
reactions45 as a potential biologically active scaffold. Prompt by
these findings and in continuation of our studies on the synthesis
of N, S containing heterocycles46-53 we decided to prepare a
group of pyrimido[4,5-b][1,5]benzothiazepine derivatives, which
Scheme 1. General rout for the preparation of pyrimido[4,5-
b][1,5]benzothiazepine derivatives.
have
been
largely
overlooked
as
a
class
of
pyrimidobenzothiazepine.
Displacement of the 6- chlorine atom of 2a-i with 2-
aminobenzenethiol 3 occurred at 0-50C temperature in benzene
to give products 4a-i. The products of this reaction concentrated
and then underwent an intramolecular cyclization in boiling
acetonitrile without further purification to give final products. The
remaining benzene in the concentrated products 4a-i plays an
important role on the removal of the produced water during the
cyclization reaction in acetonitrile. The structural assignment of
compounds 5a-i based upon the spectral and microanalytical
data. The IR spectra did not exhibit the stretching vibration
bands at 3450&3300 cm-1 (broad, NH2) or 1660cm-1 (sharp,
C=O) due to precursors but showed a sharp band at 1570 cm-1
for C=N absorption belonging to products. Further proof came
from the 1H NMR spectra, which showed the disappearance of a
sharp 1H signal at , 10.2 ppm belonging to CHO moiety of
precursors 2a-i and the appearance of a new sharp 1H signal at
, 7.5 ppm assignable to C5H of products 5a-i indicating the
construction of a [1,5]benzothiazine ring around the pyrimidine
nucleus. More proof came from mass spectra, which verified the
Results and Discussion
Our first attemt for the preparation of pyrimido[4,5- b][1,
5]benzodiazepine
was
the
condensation
of
4,6-
Department of Chemistry
Ahvaz Branch, Islamic Azad University
Ahvaz 61349-68875
Iran
E-mail: nikpour@iauahvaz.ac.ir
dichloropyrimidine-5-carbaldehyde
154
with
2-
aminobenzenethiol 3, which achieved an insoluble green
product even in various temperatures. It seems that both SH and
NH2 moieties of 2- aminobenzenethiol 3, replaced over the
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disappearance of isotopic effect of Chlorine atom of precursor’s
2a-i but showed a negligible isotopic effect due to Sulfur atom of
products 5a-i. Elemental analysis of the products 5a-i showed
no significant difference with the calculated values.
(C2); 161.0 (C5); 169.1 (C4); 189.5 (N1-C-S10). Mass spectrum, m/z
(Irel, %): 282 [M]+ (20), 28 [CH2CH2]+. (100).
Anal. Calcd. For C15H14N4S: C, 63.80; H, 5.00; N, 19.84; S, 11.36 Found:
C, 63.71; H, 4.96; N, 19.73; S, 11.18.
N,N-Diethylpyrimido[4, 5- b][1, 5]benzothiazepin-4-amine 5c
Yield 1.80 g (64%), green powder, mp 181.5–183°C. IR spectrum, ν, cm–
1: 1570 (C=N); 2960, 2900 (CH2, CH3).
1H NMR spectrum, δ, ppm (J, Hz): 1.01 (6H, t, J = 19.0, (CH3CH2)2N);
3.21 (4H, q, J = 19.0, (CH3CH2)2N); 7.05-7.20 (4H, m, C7H-C10H); 7.55
(1H, s, C5H); 8.45 (1H, s, C2H). 13C NMR spectrum, δ, ppm: 13.1
((CH3CH2)2N); 45.1 ((CH3CH2)2N); 104.6 (C4-C-C5); 123.1 (C7); 127.0
(C8); 128.0 (C9); 131.0 (C10); 136.1 (S-C-C10); 154.1 (N6-C-C7); 159.1
(C2); 161.0 (C5); 169.1 (C4); 189.5 (N1-C-S10). Mass spectrum, m/z
(Irel, %): 284 [M]+ (22), 28 [CH2CH2]+. (100). Anal. Calcd. For C15H16N4S:
C, 63.35; H, 5.67; N, 19.70; S, 11.28 Found: C, 63.22; H, 5.61; N, 19.58;
S, 11.15.
Conclusions
In conclusion, treatment of 4-(substitutedamino)-6-chloro-
pyrimidine-5-carbaldehydes
benzene and then in boiling acetonitril is an efficient route to
pyrimido[4,5-b][1,5]benzothiazepin ederivatives.
with
2-aminobenzenethiol
in
Experimental Section
4-(Piperidin-1-yl)pyrimido[4, 5- b][1, 5]benzothiazepine 5d
Yield 1.92 g (65%), green powder, mp 141–143°C. IR spectrum, ν, cm–1:
1570 (C=N); 2960, 2900 (CH2).
1
IR spectra obtained on a 4300 Shimadzu spectrometer in KBr pellets. H
NMR (300 MHz) and 13C NMR (75 MHz) spectra of products were carried
out on Bruker Avance spectrometer in Chloroform-d (CDCl3) with
tetramethylsilane (TMS) as an internal standard. Electron ionization mass
spectra obtained on a Varian Mat CH-7 instrument at 70 eV. Elemental
analysis obtained on a Thermo Finnigan Flash EA microanalyzer. Melting
points were determined on an Electrothermal 9100 apparatus.
4-(Substitutedamino)- pyrimido[4, 5- b][1, 5]benzothiazepine 5a-i
(General method).
1H NMR spectrum, δ, ppm (J, Hz): 1.50 (6H, m, ((CH2)3(CH2)2-N); 3.51
(4H, t, J = 16.1, ((CH2)3(CH2)2-N); 7.05-7.20 (4H, m, C7H-C10H); 7.56 (1H,
s, C5H); 8.44 (1H, s, C2H). 13C NMR spectrum, δ, ppm: 25.2
(CH2(CH2CH2)2N); 25.7 (CH2(CH2CH2)2N); 52.1 (CH2(CH2CH2)2N; 104.6
(C4-C-C5); 123.1 (C7); 127.1 (C8); 128.0 (C9); 131.1 (C10); 136.1 (S-C-
C10); 154.0 (N6-C-C7); 159.0 (C2); 161.1 (C5); 169.0 (C4); 189.5 (N1-C-
S10). Mass spectrum, m/z (Irel, %): 296 [M]+ (25), 28 [CH2CH2]+. (100).
Anal. Calcd. For C16H16N4S: C, 64.84; H, 5.44; N, 18.90; S, 10.82 Found:
C, 64.95; H, 5.48; N, 18.81; S, 10.35.
2-Aminobenzenethiol (1.25gr, 10mmol) added to a solution of each
compounds 2a-i (10mmol) and triethylamine (1.01gr, 10mmol) in
benzene (100ml) in 0–5°C and stirred for 4 hours. The reaction`s volume
decreased under reduced pressure to around 30ml and then dissolved in
acetonitrile (70ml) and refluxed for 8 hours. Solvent removed under
reduced pressure and the residue purified by twice crystallization from
ethanol to obtain products 5a-i.
4-(4-Methylpiperazin-1-yl)pyrimido[4, 5- b][1, 5]benzothiazepine 5e
Yield 1.52 g (49%), green powder, mp 128–129°C. IR spectrum, ν, cm–1:
1
1580 (C=N); 2960, 2900 (CH2, CH3). H NMR spectrum, δ, ppm (J, Hz):
2.03 (3H, S, CH3-N); 2.18 (4H, t, J = 16.1, (CH2)2NCH3); 3.59 (4H, t, J =
16.1, (CH2CH2)2N); 7.05-7.20 (4H, m, C7H-C10H); 7.56 (1H, s, C5H); 8.44
(1H, s, C2H). 13C NMR spectrum, δ, ppm: 44.1 (N-CH3); 46.5
((CH2)2NCH3); 56.1 ((CH2CH2)2N); 104.6 (C4-C-C5); 123.0 (C7); 127.0
(C8); 128.1 (C9); 131.1 (C10); 136.1 (S-C-C10); 154.0 (N6-C-C7); 159.0
(C2); 161.1 (C5); 169.0 (C4); 189.5 (N1-C-S10). Mass spectrum, m/z
(Irel, %): 311 [M]+ (35), 28 [CH2CH2]+. (100). Anal. Calcd. For C16H17N5S:
C, 61.71; H, 5.50; N, 22.49; S, 10.30 Found: C, 61.57; H, 5.52; N, 22.37;
S, 10.18.
4-(Morpholin-4-yl)pyrimido[4, 5- b][1, 5]benzothiazepine 5a
Yield 1.73 g (58%), green powder, mp 137.5–139°C. IR spectrum, ν, cm–
1: 1570 (C=N); 2960, 2900 (CH2).
1H NMR spectrum, δ, ppm (J, Hz): 3.52 (4H, t, J = 16.1, (CH2)2N); 3.70
(4H, t, J = 16.1, (CH2)2O); 7.05-7.20 (4H, m, C7H-C10H); 7.56 (1H, s,
C5H); 8.44 (1H, s, C2H). 13C NMR spectrum, δ, ppm: 52.5 ((CH2)2N); 66.7
((CH2)2O); 104.6 (C4-C-C5); 123.0 (C7); 127.0 (C8); 128.1 (C9); 131.1
(C10); 136.0 (S-C-C10); 154.1 (N6-C-C7); 159.0 (C2); 161.1 (C5); 169.0
(C4); 189.5 (N1-C-S10). Mass spectrum, m/z (Irel, %): 298 [M]+ (31), 28
[CH2CH2]+. (100). Anal. Calcd. For C15H14N4OS: C, 60.38; H, 4.73; N,
18.78; S, 10.75 Found: C, 60.59; H, 4.79; N, 18.72; S, 10.52.
4-(4-Phenylpiperazin-1-yl)pyrimido[4, 5- b][1, 5]benzothiazepine 5f
Yield 1.49 g (40%), green powder, mp 202–203°C. IR spectrum, ν, cm–1:
1
1570 (C=N); 2950, 2900 (CH2). H NMR spectrum, δ, ppm (J, Hz): 3.22
(4H, t, J = 16.1, (CH2)2NPh); 3.61 (4H, t, J = 16.1, (CH2CH2)2N); 7.02-
7.53 (10H, m, Aromatic); 8.45 (1H, s, C2H). 13C NMR spectrum, δ, ppm:
46.5 ((CH2)2NCH3); 56.1 ((CH2CH2)2N); 104.6 (C4-C-C5); 114.1 (C2 of
Phenyl), 118.5 (C4 of Phenyl), 123.0 (C7); 127.0 (C8); 128.1 (C9); 129.3
(C3 of Phenyl), 131.1 (C10); 136.1 (S-C-C10); 149.3 (C1 of Phenyl), 154.0
(N6-C-C7); 159.0 (C2); 161.1 (C5); 169.0 (C4); 189.5 (N1-C-S10). Mass
spectrum, m/z (Irel, %): 373 [M]+ (21), 28 [CH2CH2]+. (100). Anal. Calcd.
For C21H19N5S: C, 67.53; H, 5.13; N, 18.75; S, 8.59 Found: C, 67.69; H,
4-(Pyrrolidin-1-yl)pyrimido[4, 5- b][1, 5]benzothiazepine 5b
Yield 1.80 g (64%), green powder, mp 163.5–164°C. IR spectrum, ν, cm–
1: 1570 (C=N); 2960, 2900 (CH2).
1H NMR spectrum, δ, ppm (J, Hz): 1.53 (4H, t, J = 16.1, (CH2CH2)2N);
3.51 (4H, t, J = 16.1, (CH2CH2)2N); 7.05-7.20 (4H, m, C7H-C10H); 7.56
(1H, s, C5H); 8.44 (1H, s, C2H). 13C NMR spectrum, δ, ppm: 25.5
((CH2CH2)2N); 52.1 ((CH2CH2)2N); 104.6 (C4-C-C5); 123.0 (C7); 127.1
(C8); 128.1 (C9); 131.0 (C10); 136.0 (S-C-C10); 154.1 (N6-C-C7); 159.1
5.03; N, 18.54; S, 8.41.
N-Ethylpyrimido[4,5-b][1,5]benzothiazepin-4-amine 5g
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Yield 1.70 g (66%), green powder, mp 170–172°C. IR spectrum, ν, cm–1:
the treatment of diabetic nephropathy. Int. J. Diabet. Metabol. 2005, 13,
76-82.
1570 (C=N); 2960, 2900 (CH2, CH3); 3350 (NH).
1H NMR spectrum, δ, ppm (J, Hz): 1.02 (3H, t, J = 19.0, CH3CH2NH);
3.24 (2H, q, J = 19.0, CH3CH2NH); 7.05-7.20 (4H, m, C7H-C10H); 7.55
(1H, s, C5H); 8.45 (1H, s, C2H); 8.70 (1H, broad, NH). 13C NMR spectrum,
δ, ppm: 13.1 (CH3CH2NH); 45.2 (CH3CH2NH); 104.5 (C4-C-C5); 123.2
(C7); 127.0 (C8); 128.1 (C9); 131.0 (C10); 136.1 (S-C-C10); 154.1 (N6-C-
C7); 159.1 (C2); 161.0 (C5); 169.1 (C4); 189.5 (N1-C-S10). Mass spectrum,
m/z (Irel, %): 256 [M]+ (30), 28 [CH2CH2]+. (100). Anal. Calcd. For
C13H12N4S: C, 60.91; H, 4.72; N, 21.86; S, 12.51 Found: C, 60.73; H,
4.80; N, 21.65; S, 12.35.
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Medical Publishers (LTD) 465.
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(Eds.) Goodman and Gilman’s The Pharmacological Basis of
Therapeutics 809-821.
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angiotensin converting enzyme by (R)-3-(S)-1-carboxy-5-(4-piperidyl)
pentyl amino-4-oxo-2,3,4,5-tetra- hydro-1,5-benzothiazepine-6-acetic
acid (CV-5975),
a
non-sulfhydryl compound. Japanese J.
N-Benzylpyrimido[4,5-b][1,5]benzothiazepin-4-amine 5h
Pharmacology.1988, 48, 323-330.
Yield 2.35 g (74%), green powder, mp 185-186°C. IR spectrum, ν, cm–1:
1570 (C=N); 2950, 2900 (CH2); 3360 (NH). 1H NMR spectrum, δ, ppm (J,
Hz): 4.35 (2H, s, CH2NHPh); 7.02-7.2 (9H, m, Aromatic); 7.55 (1H, s,
C5H); 8.45 (1H, s, C2H); 8.70 (1H, broad, NH). 13C NMR spectrum, δ,
ppm: 46.2 (CH2NHPh); 104.6 (C4-C-C5); 114.3 (C2 of Phenyl), 118.7 (C4
of Phenyl), 123.0 (C7); 127.0 (C8); 128.1 (C9); 129.1 (C3 of Phenyl), 131.1
(C10); 136.1 (S-C-C10); 149.1 (C1 of Phenyl), 154.0 (N6-C-C7); 159.0 (C2);
161.1 (C5); 169.0 (C4); 189.5 (N1-C-S10). Mass spectrum, m/z (Irel, %):
318 [M]+ (26), 28 [CH2CH2]+. (100). Anal. Calcd. For C18H14N4S: C,
67.90; H, 4.43; N, 17.60; S, 10.07 Found: C, 67.71; H, 4.56; N, 17.34; S,
[9]15. M. Kaburaki, H. Yabana, H. Doi, K. Nagata, H. Narita, and S. Murata
The Mechanism of the Increasing Action of TA-993, a New 1,5-
Benzothiazepine Derivative, on Limb Blood Flow in Anesthetized Dogs:
Selective Suppression of Sympathetic Nerve Activity. J. Pharmacology
and Experimental Therapeutics. 1999, 288, 1167–1173.
[10].H. Inoue, M. Konda, T. Hashiyama, H. Otsuka, K.Takahashi, M. Gaino, T.
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Sulfamoylbenzamide derivatives as antiviral agents against HBV
infection WO2013/006394A1.
9.81.
N-Propylpyrimido[4,5-b][1,5]benzothiazepin-4-amine 5i
Yield 1.95 g (72%), green powder, mp 153–154°C. IR spectrum, ν, cm–1:
[13] S. M. Ford, S.Roach Lippincott's Introductory Clinical Pharmacology-1,
Lippincott Williams and Wilkins.2008, 281-293.
1570 (C=N); 2960, 2900 (CH2, CH3); 3350 (NH).
1H NMR spectrum, δ, ppm (J, Hz): 1.00 (3H, t, J = 19.0, CH3CH2CH2NH);
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1.64 (2H, sextet,
CH3CH2CH2NH); 3.21 (2H, t,
J
=
19.0,
CH3CH2CH2NH); 7.05-7.20 (4H, m, C7H-C10H); 7.55 (1H, s, C5H); 8.45
(1H, s, C2H); 8.70 (1H, broad, NH). 13C NMR spectrum, δ, ppm: 11.5
(CH3CH2CH2NH); 23.5 (CH3CH2CH2NH); 47.5 ( CH3CH2CH2NH); 104.6
(C4-C-C5); 123.1 (C7); 127.0 (C8); 128.0 (C9); 131.0 (C10); 136.1 (S-C-
C10); 154.1 (N6-C-C7); 159.1 (C2); 161.0 (C5); 169.1 (C4); 189.5 (N1-C-
S10). Mass spectrum, m/z (Irel, %): 284 [M]+ (22), 28 [CH2CH2]+. (100).
Anal. Calcd. For C15H16N4S: C, 63.35; H, 5.67; N, 19.70; S, 11.28 Found:
C, 63.22; H, 5.61; N, 19.58; S, 11.15.
[16] S. M. Ford, S. Roach. Lippincott's Introductory Clinical Pharmacology-1.
2008, 304-309.
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2,3-dihydro-1,5-benzothiazepines
as
cholinesterase
inhibitors.
Medicinal Chemistry Research. 2011, DOI 10.1007/s00044-011-9754-6.
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Acknowledgements
[19] K. Arya, A. Dandia. The expedient synthesis of 1,5-benzothiazepines as a
family of cytotoxic drugs. Bioorg. Med. Chem. Lett.. 2008, 18, 114–119.
[20] F. L. Ansari, F. Iftikhar, I. U. Haq et.al. Solid-phase synthesis and
Financial support of this research by Ahvaz Branch, Islamic
Azad University gratefully acknowledged.
biological evaluation of
a
parallel library of 2,3-dihydro-1,5-
benzothiazepine. Bioorg. Med. Chem. 2008, 16, 7691-7697.
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Nori. Microwave assisted synthesis.and biological evaluation of a series
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European Journal of Chemistry. 2014, 5, 138‐143.
Keywords:
aminobenzenethiol,
cyclocondensation, fused benzothiazepines.
4,6-Dichloropyrimidine-5-carbaldehyde,
2-
pyrimido[4,5-b][1,5]benzothiazepine,
[22] P.Zhang, H. R.Hub,S. H. Bian, Z. H. Huang, Y. Chu, D. Y.Ye. Design,
synthesis and biological evaluation of benzothiazepinones (BTZs) as
novel non-ATP competitive inhibitors of glycogen synthase kinase-3β
(GSK-3β). European Journal of Medicinal Chemistry. 2013,61, 95-103.
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azepinones.2014 WO patent WO2014/023708A1.
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