Synthesis of 2-pyridyl-substituted derivatives of 7-benzyl-5,6,7,8-tetra- hydropyrido[3,4-d]pyrimidine

Article abstract of DOI:10.1007/s10593-007-0200-0

A method has been developed for the synthesis of 2-pyridyl-substituted derivatives of 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine based on the condensation of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate with pyridyl-2-, pyridyl-3-, and pyridyl-4-c

Full text of DOI:10.1007/s10593-007-0200-0

Chemistry of Heterocyclic Compounds, Vol. 43, No. 10, 2007
SYNTHESIS OF 2-PYRIDYL-SUBSTITUTED
DERIVATIVES OF 7-BENZYL-5,6,7,8-TETRA-
HYDROPYRIDO[3,4-d]PYRIMIDINE
A. Yu. Kuznetsov and S. V. Chapyshev
A method has been developed for the synthesis of 2-pyridyl-substituted derivatives of 7-benzyl-5,6,7,8-
tetrahydropyrido[3,4-d]pyrimidine based on the condensation of ethyl 1-benzyl-3-oxopiperidine-
4-carboxylate with pyridyl-2-, pyridyl-3-, and pyridyl-4-carboxamidines and subsequent reactions of
7-benzyl-2-pyridyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-ones with trifluoromethanesulfonic
anhydride and secondary amines.
Keywords: ethyl 1-benzyl-3-oxopiperidine-4-carboxylate, pyridinecarboxyamidines, pyrido[3,4-d]pyrimi-
dines, condensation.
Pyrido[3,4-d]pyrimidines have high biological activity, in particular they selectively inhibit tyrosine
kinase, completely inhibit the growth of many forms of malignant tumors [1-3]. Separate examples of this class
of compounds are antagonistic to α1-adrenoreceptors and are used in medicine for the treatment of nervous
disorders [4] and also effectively inhibit the activity of dehydrofolate reductase, and cause the death of many
pathogenic microorganisms [5]. The direction and effectiveness of the biological effects of pyrido[3,4-d]-
pyrimidines frequently depends on the substituents in the pyridopyrimidine nucleus. In previous papers we have
shown that suitable method for the synthesis of pyrido[3,4-d]pyrimidines is the condensation of ethyl 1-benzyl-
3-oxopiperidine-4-carboxylate (1) with morpholine- and pyrrolidine-substituted carboxamidines, which permit
the preparation in high yields of derivatives of 7-benzyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-ones
[6, 7]. In this work we have studied the condensation of the keto ester 1 with pyridinecarboxamidines 2a-c and
the reactions of the intermediate 7-benzyl-2-pyridyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-ones 3a-c
with trifluoromethanesulfonyl anhydride and amines.
Boiling an ethanolic solution of the keto ester 1 with an equimolar amount of amidines 2a-c in the
presence of 3 equivalents of EtONa for 3 h led to the formation of new compounds. According to their elemental
analyses, IR, 1H NMR spectroscopy and mass spectrometry (Tables 1-3), the compounds formed are derivatives
of 7-benzyl-2-pyridyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-ones 3a-c, in yields of 71-76%.
The pyridopyrimidines 3a-c have promise as starting materials for the synthesis of derivatives of
7-benzyl-2-pyridyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine. Thus by use of the reaction of compounds 3a-c
with trifluoromethanesulfonic anhydride with amines, we obtained 4-amino-7-benzyl-2-pyridyl-5,6,7,8-tetra-
hydropyrido[3,4-d]pyrimidines 5a-f in high yields.
__________________________________________________________________________________________
Institute for Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka 142432,
Moscow Region; e-mail: chap@icp.ac.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10,
1556-1561, October, 2007. Original article submitted June 6, 2006.
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0009-3122/07/4310-1320©2007 Springer Science+Business Media, Inc.

Table 1. Characteristics of Compounds 3a-c and 5a-f
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp,°C
Yield, %
С
H
N
3a
3b
C19H18N4O
C19H18N4O
71.51
71.68
5.84
5.70
17.38
17.60
149-150
232-234
71
76
71.48
71.68
71.46
71.68
74.12
74.36
71.04
71.29
72.31
72.43
73.93
74.12
74.01
74.29
73.71
73.96
5.93
5.70
5.87
5.70
6.99
6.78
6.73
6.50
7.44
7.29
6.47
6.22
6.70
6.46
7.34
7.28
17.44
17.60
17.46
17.60
18.89
18.85
18.14
18.07
20.25
20.27
16.13
16.01
19.29
19.25
18.95
18.75
3c
5a
5b
5c
5d
5e
5f
C19H18N4O
C23H25N5
C23H25N5O
C25H30N6
C27H27N5O
C27H28N6
C23H27N5
210-211
197-199
163-164
139-140
146-148
128-129
91-92
72
75
74
71
69
70
68
Table 2. Spectra of Compounds 3a-c and 5a-f
Com-
pound
IR spectrum (KBr), ν, cm-1
Mass spectrum, m/z (Irel %)
3a
3b
3c
3320 (NH), 1730 (C=O), 1610, 1590, 1580, 1565, 318 [M]+ (100), 225 (55), 174 (5)
1540 (C=N, C=C)
3350 (NH), 1725 (C=O), 1610, 1595, 1585, 1570, 318 [M]+ (100), 225 (5)
1545 (C=N, C=C)
3350 (NH), 1725 (C=O), 1610, 1590, 1580, 1570, 318 [M]+ (100), 225 (5), 174 (5)
1545 (C=N, C=C)
5a
5b
5c
5d
1610, 1595, 1580, 1570, 1540 (C=N, C=C)
1610, 1595, 1575, 1565, 1535 (C=N, C=C)
1610, 1595, 1580, 1570, 1540 (C=N, C=C)
371 [M]+ (100), 253 (10)
387 [M]+ (100)
414 [M]+ (100), 177 (8)
437 [M]+ (100)
3280 (NH), 1610, 1600, 1595, 1580, 1565,
1530 (C=N, C=C)
5e
5f
1610, 1600, 1595, 1575, 1565, 1535 (C=N, C=C)
1610, 1595, 1575, 1565, 1535 (C=N, C=C)
436 [M]+ (100), 318 (5)
373 [M]+ (100)
In the 1H NMR spectra of all the compounds 5a-f the signals of the methylene protons of the piperidine
ring and the benzyl unit appear at 2.8 (t, J = 7.5 Hz, H-5), 2.9 (t, J = 7.5 Hz, H-6), 3.7 (s, H-8), 3.3-3.5 ppm
(CH2Ph) and five aromatic protons of the phenyl group at 7.2-7.4 ppm (Table 3), typical for all derivatives of
1
7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine [6]. In comparing the H NMR spectra of compounds 3a-c
and 5a-f it is interesting to note that the methylene protons in positions 5 and 6 of compounds 3a-c are
magnetically equivalent and appear as four-proton singlet at 2.75 ppm (Table 3).
Evidently amination of these compounds at position 4 is accompanied by considerable conformational
changes in the annelated piperidine ring, as a result of which the methylene protons in positions 5 and 6 in
compounds 5a-f become magnetically nonequivalent.
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O
O
O
H2N
HN
NaOEt
EtOH
NH
OEt
R
+
Ph
N
Ph
N
N
R
HCl
1
3a–c
2a–c
(F3CSO2)2O
NR1R2
OSO2CF3
N
N
N
HNR1R2
Ph
N
Ph
N
N
R
R
4a–c
5a–f
2–4 a R = 2-Py, b R = 3-Py, c R = 4-Py;
b NR1R2 =
1
2
pyrrolidyl,
morpholyl;
5 a–e R = 2-Py, a NR R =
OMe
N
H
c NR1R2 =
N
N
Et
d NR1R2 =
Me
N
f NR1R2 = NEt2
e NR1R2 =
N
Analysis of the mass spectra (Table 2) shows that compounds 3a-c and 5a-f are uniformly stable to an
electron impact, giving in most cases only molecular ion peaks on a background of a small number of peaks of
fragmentation ions of low intensity (< 5%). The presence in the mass spectra of compounds 3a-c of noticeable
fragmentation ion peaks with a mass (m/z) of 225 (Irel 5-55%) shows that one of the initial stages of the
fragmentation of these compounds under an electron impact includes the cleavage of the benzyl unit and the
formation of relatively stable ions of the protonated 2-pyridylpyrido[3,4-d]pyrimidin-4-ones.
The study carried out shows that the reaction of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate with
pyridinecarboxamidines leads to production of 7-benzyl-2-pyridyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]-
pyrimidin-4-ones, which can be used further in the synthesis of various derivatives of 5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidines.
EXPERIMENTAL
1
IR spectra were recorded with a Specord M-80 spectrometer, H NMR spectra on a Bruker AMX-400
(400 MHz) instrument with TMS as internal standard. Mass spectra were recorded on a Finnigan MAT-90
instrument with an ionization energy of 70 eV. Silica gel (L 40/100) was used for column chromatography. The
keto ester 1 used in this work was from Acros.
The method of preparing the amidines 2a-c was described elsewhere [7].
7-Benzyl-2-pyridyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-ones
3a-c.
An
amidine
hydrochloride 2a-c (23.6 g, 150 mmol) was added in small portions to a stirred solution of NaOEt, made from
Na (7.0 g, 300 mmol) and absolute ethanol (300 ml), followed by the keto ester 1 (35.5 g, 148 mmol) added
dropwise. The mixture was boiled for 3 h, the solvent was removed in vacuum, and a saturated solution of
ammonium chloride was added to the residue. The material insoluble in water was filtered off, washed with
water, methanol, and then ether, and dried in the air.
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4-Amino-7-benzyl-2-pyridyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidines 5a-f. Trifluromethane-
sulfonic anhydride (4.92 g, 12 mmol) was added dropwise with stirring to a suspension of compound 3a-c (3.2 g,
10 mmol) in pyridine (50 ml) cooled to -20°C, after which the temperature was slowly increased to ~20°C,
stirring was continued for 30 min, then the mixture was poured into water (500 ml). The precipitate was filtered
off, washed with water and dried in the air. The dried precipitate was dissolved in dry dioxane (150 ml). K2CO3
(4 g, 30 mmol) and the corresponding amine (15 mmol) were added to this solution which was boiled for 3 h,
cooled, and poured into water (300 ml), extracted with ethyl acetate. The extract was dried over Na2SO4 and
chromatographed on a short column. The solvent was removed in vacuum, the residue was dried in the air and
recrystallized from ethyl acetate.
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