Synthesis of substituted 4-aminothieno[2,3-d]-, 4-aminothieno[3,2-d]- and 4-aminothieno[3,4-d]pyrimidines

Article abstract of DOI:10.1007/s10593-012-1095-y

A study was carried out on the nucleophilic cleavage of the lactam bond in 4-amino(pyrrolidino, piperidino, morpolino)thieno[2,3-d]-, -[3,2-d]-, and -[3,4-d]pyrimido[1,2-b]isoquinolin-11-ones. This bond is readily cleaved upon heating in methanolic NaOH a

Full text of DOI:10.1007/s10593-012-1095-y

Chemistry of Heterocyclic Compounds, Vol. 48, No. 7, October, 2012 (Russian Original Vol. 48, No. 7, July, 2012)
SYNTHESIS OF SUBSTITUTED
4-AMINOTHIENO[2,3-d]-, 4-AMINOTHIENO[3,2-d]-
AND 4-AMINOTHIENO[3,4-d]PYRIMIDINES
A. V. Zadorozhny*
A study was carried out on the nucleophilic cleavage of the lactam bond in 4-amino(pyrrolidino,
piperidino, morpolino)thieno[2,3-d]-, -[3,2-d]-, and -[3,4-d]pyrimido[1,2-b]isoquinolin-11-ones. This
bond is readily cleaved upon heating in methanolic NaOH at reflux for 1-2 h to give previously
unreported 4-amino-2-(o-carboxyphenylmethyl)thienopyrimidines. Replacement of the amine group by
an OH group is possible under the reaction conditions, leading to the corresponding, already reported
2-(o-carboxyphenylmethyl)-4-oxothienopyrimidines. Prolonged refluxing (8-12 h) resulted in
oxothienopyrimidines as the major products of the transformations of all the thienopyrimido-
isoquinolinones studied. Biological activity predictions of these new products were compared in silico.
Keywords: positional-isomeric substituted thienopyrimidines, calculation of biological activity,
nucleophilic cleavage of the lactam bond, nucleophilic substitution.
In a continuation of our study of 2-(o-carboxyphenylmethyl)thienopyrimidines with various types of
thiophene and pyrimidine ring fusion [1, 2], we now describe the synthesis of new 4-amino(pyrrolidino,
piperidino, morpholino) derivatives of this group.
We should note that among known 4-aminothienopyrimidines, only derivatives 1 [3], 2 [4], and 3 [5]
are similar to some extent to the above mentioned amino derivatives targeted for synthesis.
O
O
N
Me
N
N
N
N
Me
N
NC
COOEt
N
N
S
Me
N
S
S
COOEt
2
1
COOMe
3
_______
*To whom correspondence should be addressed, e-mail: shura_zd@ukr.net.
1Enamine Ltd., 23 Aleksandra Matrosova St., Kyiv 01103, Ukraine.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1107-1112, July, 2012. Original
article submitted March 23, 2011.
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0009-3122/12/4807-1028©2012 Springer Science+Business Media New York

Of these compounds, ester 3 is the most similar in structure and the most interesting from the viewpoint
of possible biological activity; this compound has been patented as a type 7 phosphodiesterase inhibitor (PDE7,
IC50 less than 1 μmol) and can be used both in therapy and in the prevention of the development of such
diseases as asthma, atopic dermatitis, rheumatoid arthritis, psoriasis etc. [5].
Nucleophilic cleavage of the C(11)–N(12) lactam bond of previously synthesized [6, 7] substituted
thienopyrimido[1,2-b]isoquinolin-11-ones 4a-c, 5a-c, and 6a with [2,3-d], [3,2-d], and [3,4-d] fusion of the
thiophene and pyrimidine rings has been studied for the synthesis of the target compounds (series A, B, and C,
respectively).
R
4
R
O
·HCl
4
5
3
1) NaOH
MeOH
, 1–2 h
N 3
N 5
NH
6
2
S
S
S
6
N
O
N
11
N
O
+
7
1
2) HCl
1
7
8
3'
4'
OH
O
OH
6'
10
9
5'
10 (A), 11 (B), 12 (C)
7a–c (A), 8a–c (B), 9a (C)
4a–c (A), 5a–c (B),
6a (C)
a R = pyrrolidino, b R = piperidino, c R = morpholino
Me
S
S
=
(A),
(B),
(C)
S
Me
S
It is known that the action of 5 N sodium hydroxide in ethanol readily cleaves the lactam bond in
2-(pyridin-2-yl)-1,2,4-triazolo[1,5-b]isoquinolin-5(10H)one [8] and 6,11-dihydrobenzimidazo[1,2-b]isoquino-
lin-11-one [9].
In the present work, we show that the action of 5 N methanolic NaOH also smoothly opens the lactam
bond in thienopyrimido[1,2-b]isoquinolinones 4a-c, 5a-c, and 6a to give the desired corresponding substituted
thienopyrimidines isolated as hydrochloride salts 7a-c, 8a-c, and 9a in 60-90% yield. In the case of the starting
4-piperidino and 4-morpholino derivatives 4b and 4c, we also obtained the already reported 2-(o-carb-
oxyphenylmethyl)-4-oxothienopyrimidine 10 in a yield of 10% and 20%, respectively. The sample of
1
thienopyrimidine 10 was identical in its melting point, IR spectrum, and H NMR spectrum to an authentic
sample [1]. A thin-layer chromatographic analysis of the reaction mixtures indicated that, under the reaction
conditions, replacement of the amine group at C-4 of the starting reagents 4b and 4c by an OH group and
opening of the lactam fragment take place virtually simultaneously, while opening of the lactam bond is the
primary process in all other cases. The analysis in this case is simple and illustrative in light of the large
difference in chromatographic mobility in the 1:4 methanol–toluene system: Rf 0.70-0.80 for the starting
compounds 4-6, Rf 0.30-0.33 for the resultant hydrochlorides 7-9, and Rf 0.15-0.20 for the 4-oxopyrimidines
10-12.
Prolonged heating of the reaction mixtures at reflux for 8-12 h gave the corresponding 4-oxo derivatives
1
10-12 in quantitative yield. These products were identical in their melting point, IR spectra, and H NMR
spectra to authentic samples [1, 2].
The composition and structure of the new products 7a-c (series A), 8a-c (series B), and 9a (series C)
1
were supported by elemental analysis as well as IR and H NMR spectroscopy (Table 1). Comparison of the
spectral data of series A-C compounds identically substituted in the pyrimidine fragment shows that a change of
the thiophene ring sulphur atom position does not have a significant effect on the 1H NMR spectra. On the other
hand, a marked increase in the frequency of the C=N band by an average of 14 cm-1 is observed in the IR
spectra of series B compounds in comparison with the spectra of their series A analogs.
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TABLE 2. Biological Activity Evaluation Results* for the Products 8a-c
and 9a
Compound
Ра
Рі
0.883
0.884
0.848
0.857
0.005
0.005
0.009
0.008
8а
8b
8c
9a
_______
*Assumed activity is D4 receptor agonist.
In order to evaluate the biological potential of products 7a-c (series A), 8a-c (series B), and 9a (series
C) (all in base form), we calculated the range of their biological activity using the PASS program [10-12]. The
final result is given as the probability that a given compound will display activity (Pa) or inactivity (Pi) (100%
probability = 1.000). The spectrum of more than 3000 types of activity for each compound was calculated; the
activity threshold (Pa) was chosen as 0.80, while the inactivity threshold (Pi) was chosen as 0.2. Analysis of the
calculation results unexpectedly indicated that compounds in the series A did not attain the threshold of Pa. On
the other hand, quite high indices (Table 2) were obtained for compounds in the series B and also for the
compound 9a (series C). A high level of agonist activity is predicted for these compounds towards the type 4
dopamine receptors [13].
Thus, a convenient method is proposed for the preparation of 4-amino-2-(o-carboxyphenyl-
methyl)thienopyrimidines with various types of thiophene and pyrimidine ring fusion.
EXPERIMENTAL
The IR spectra were recorded on a Perkin Elmer Spectrum BX spectrometer with a Pike Attenuated Total
Reflectance accessory. The 1H NMR spectra of solutions of the products in DMSO-d6 were obtained on a Bruker
Avance DRX-500 spectrometer at 500 MHz for compounds 7a-c and 8a-c and a Varian Mercury-400 spectrometer
at 400 MHz for compound 9a with TMS as internal standard. The purity of the products was checked with an
Agilent 1100 LC/MS equipped with an Agilent LC/MSD SL detector. The sample was introduced in a
trifluoroacetic acid matrix. The mass spectra were obtained with electron impact ionization. The elemental analysis
was carried out on a Vario MICRO cube universal elemental analyzer. The melting points were determined in
Pyrex capillaries in a Thiele tube apparatus and were corrected. Thin-layer chromatographic analysis was carried
out on Macherey-Nagel silica gel (0.2 mm, UV-254) using 1:4 methanol–toluene as the eluent.
Action of Methanolic NaOH on 4-Aminothienopyrimido[1,2-b]isoquinolin-11-ones 4a-c, 5a-c, and
6a (General Method). Compound 4a-c, 5a-c, or 6a (5 mmol) was added to 5 N methanolic sodium hydroxide
solution (25 ml). The suspension was heated at reflux for 1-2 h until dissolution. The solution was cooled and
brought to pH 2 by adding concentrated hydrochloric acid. The precipitate formed over 24 h was filtered off and
treated with hot acetonitrile. Traces of product 10 (formed in the case of starting compounds 4a-c), 11 (from
compounds 5a-c), or 12 (from compound 6a), which are insoluble under these conditions, were separated by hot
filtration of the mixture. Upon cooling, the filtrate gave crystals of the desired products, 7a-c, 8a-c, or 9a.
2-(5,6-Dimethyl-4-pyrrolidinothieno[2,3-d]pyrimidin-2-ylmethyl)benzoic Acid Hydrochloride (7a).
Yield 1.62 g (80%); mp 140-142 С. Rf 0.30. IR spectrum, ν, cm-1: 1681 (С=О), 1573 (C=N). Mass spectrum,
m/z: 368 [M+H-HCl]+. Found, %: C 59.56; Н 5.45; Cl 8.82; N 10.46; S 7.98. C20H22ClN3O2S. Calculated, %:
С 59.47; Н 5.49; Cl 8.78; N 10.40; S 7.94.
2-(5,6-Dimethyl-4-piperidinothieno[2,3-d]pyrimidin-2-ylmethyl)benzoic Acid Hydrochloride (7b).
Yield 1.71 g (82%); mp 200-202С. Rf 0.31. IR spectrum, ν, cm-1: 1697 (С=О), 1570 (C=N). Mass spectrum,
m/z: 382 [M+H-HCl]+. Found, %: С 60.45; Н 5.89; Cl 8.40; N 9.90; S 7.78. C21H24ClN3O2S. Calculated, %:
С 60.35; Н 5.79; Cl 8.48; N 10.05; S 7.67.
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2-(5,6-Dimethyl-4-morpholinothieno[2,3-d]pyrimidin-2-ylmethyl)benzoic Acid Hydrochloride
(7c). Yield 1.26 g (60%); mp 170-172С. Rf 0.32. IR spectrum, ν, cm-1: 1685 (С=О), 1567 (C=N). Mass
spectrum, m/z: 384 [M+H-HCl]+. Found, %: С 57.46; Н 5.15; Cl 8.38; N 10.16; S 7.78. C20H22ClN3O3S.
Calculated, %: С 57.21; Н 5.28; Cl 8.44; N 10.01; S 7.64.
2-(4-pyrrolidinothieno[3,2-d]pyrimidin-2-ylmethyl)benzoic Acid Hydrochloride (8a). Yield 1.69 g
(90%); mp 235-237С. Rf 0.30. IR spectrum, ν, cm-1: 1703 (С=О), 1587 (C=N). Mass spectrum, m/z: 340
[M+H-HCl]+. Found, %: С 57.66; Н 4.75; Cl 9.33; N 11.36; S 8.68. C18H18ClN3O2S. Calculated, %: С 57.52;
Н 4.83; Cl 9.43; N 11.18; S 8.53.
2-(4-Piperidinothieno[3,2-d]pyrimidin-2-ylmethyl)benzoic Acid Hydrochloride (8b). Yield 1.66 g
(85%); mp 135-137С. Rf 0.31. IR spectrum, ν, cm-1: 1698 (С=О), 1585 (C=N). Mass spectrum, m/z: 354
[M+H-HCl]+. Found, %: С 58.66; Н 5.15; Cl 9.14; N 10.66; S 8.38. C19H20ClN3O2S. Calculated, %: С 58.53;
Н 5.17; Cl 9.09; N 10.78; S 8.22.
2-(4-Morpholinothieno[3,2-d]pyrimidin-2-ylmethyl)benzoic Acid Hydrochloride (8c). Yield 1.70 g
(87%); mp 190-192С. Rf 0.33. IR spectrum, ν, cm-1: 1695 (С=О), 1583 (C=N). Mass spectrum, m/z: 356
[M+H-HCl]+. Found, %: С 55.16; Н 4.55; Cl 8.90; N 10.56; S 8.28. C18H18ClN3O3S. Calculated, %: С 55.17;
Н 4.63; Cl 9.05; N 10.72; S 8.18.
2-(4-Pyrrolidinothieno[3,4-d]pyrimidin-2-ylmethyl)benzoic Acid Hydrochloride (9a). Yield 1.50 g
(80%); mp 180-182С. Rf 0.31. IR spectrum, ν, cm-1: 1702 (С=О), 1578 (C=N). Mass spectrum, m/z: 340
[M+H-HCl]+. Found, %: С 57.66; Н 4.75; Cl 9.33; N 11.16; S 8.58. C18H18ClN3O2S. Calculated, %: С 57.52;
Н 4.83; Cl 9.43; N 11.18; S 8.53.
The author thanks Enamine Ltd., Kyiv, for supporting this project.
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