Synthesis of pyrido[3,4-d]pyrimidines by condensation of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate with morpholine-4-carboxamidine

Article abstract of DOI:10.1007/s10593-007-0100-3

A method has been developed for the synthesis of 4-amino-substituted 7-benzyl-2-morpholin-4-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidines by condensation of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate with morpholine-4-carboxamidine and subsequent reaction of the 7-benzyl-2-morpholin- 4-yl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one with trifluoromethanesulfonic anhydride and secondary amines.

Full text of DOI:10.1007/s10593-007-0100-3

Chemistry of Heterocyclic Compounds, Vol. 43, No. 5, 2007
SYNTHESIS OF PYRIDO[3,4-d]PYRIMIDINES BY CONDENSATION
OF ETHYL 1-BENZYL-3-OXOPIPERIDINE-4-CARBOXYLATE
WITH MORPHOLINE-4-CARBOXAMIDINE
A. Yu. Kuznetsov1, N. L. Nam2, and S. V. Chapyshev1
A method has been developed for the synthesis of 4-amino-substituted 7-benzyl-2-morpholin-4-yl-
5,6,7,8-tetrahydropyrido[3,4-d]pyrimidines by condensation of ethyl 1-benzyl-3-oxopiperidine-
4-carboxylate with morpholine-4-carboxamidine and subsequent reaction of the 7-benzyl-2-morpholin-
4-yl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one with trifluoromethanesulfonic anhydride and
secondary amines.
Keywords: Ethyl 1-benzyl-3-oxopiperidine-4-carboxylate, morpholine-4-carboxamidine, pyrido[3,4-d]-
pyrimidines, condensation.
Pyrido[3,4-d]pyrimidines show high biological activity, particularly in their selective inhibition of
tyrosine kinase fully suppressing the growth of many forms of malignant tumors [1-3]. Individual members of
this class of compounds are α1-adrenoceptor antagonists and are used in medicine for nervous dysfunction [4].
They also efficiently inhibit the action of dehydrofolate reductase causing the death of many pathogenic
microorganisms [5]. The direction and efficiency of the biological activity of the pyrido[3,4-d]pyrimidines in
general depend on the substituents in the pyridopyrimidine ring. The most common methods of synthesizing
pyrido[3,4-d]pyrimidines are the cyclization reactions of 3-acylaminoisonicotinic acid derivatives with acetic
anhydride and then ammonia [6-8] or via the condensation of 3-aminoisonicotinic acid or its esters, amides, and
nitriles with formic acid, formamide, cyanamides, amidines, or ortho esters [3, 7-9]. More rarely, pyrido-
[3,4-d]pyrimidines are prepared by the condensation of 1-benzyl-3-oxopiperidine-4-carboxylic acid esters with
amidines [4, 10], the synthetic potential of which remains largely unexplored.
With the aim of developing novel synthetic methods for pyrido[3,4-d]pyrimidines we have now studied
the condensation of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (1) with morpholine-4-carboxamidine (2) and
the subsequent reactions of the 7-benzyl-2-morpholin-4-yl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one
(3) obtained with trifluoromethanesulfonic anhydride and secondary amines.
Condensation of the keto ester 1 with an equimolar amount of the carboxamidine 2 was carried out in
ethanol with boiling using 3 equivalents of sodium ethylate as catalyst. The reaction was monitored by TLC
which showed that it was completed after 3 h and gave a new compound. According to elemental analytical, IR,
1H NMR, and mass spectroscopic analysis (Table 3) the reaction product is compound 3 (yield 87%).
__________________________________________________________________________________________
1Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka 142432,
2
Moscow Region; e-mail: chap@icp.ac.ru. K. A. Timiryazev Russian State Agrarian University, Moscow
127550; e-mail: dimlorg@timacad.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 762-
768, May, 2007. Original article submitted March 10, 2006.
640
0009-3122/07/4305-640©2007 Springer Science+Business Media, Inc.

O
O
HN
NaOEt
EtOH
OEt
O
N
+
Ph
N
H2N
2
1
O
N
(CF3SO2)2O
NH
CH2Cl2/K2CO3
Ph
N
N
O
3
NR1R2
N
OSO2CF3
N
HNR1R2
5a–i
Ph
N
Ph
N
N
N
N
N
O
6a–i
O
4
5, 6 NR1R2 = a
b
N
-i
N Pr
c
N
O
N
d
N
N
Pr
e
N
S
MeN
N
O
NH2
f
g
i
h
N
N
N
N
O
H2N
TABLE 1. Characteristics of Compounds 3 and 6a-i
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
С
H
N
3
C18H22N4O2
C22H29N5O
C22H29N5O2
C22H29N5OS
C25H36N6O
C25H36N6O
C24H32N6O2
C24H32N6O2
C26H36N6O
C26H32N6O
66.46
66.24
69.87
69.63
66.93
66.81
64.41
64.20
69.02
68.78
68.94
68.78
66.26
66.03
66.28
66.03
6.96
6.80
7.96
7.70
7.57
7.39
7.29
7.10
8.48
8.31
8.54
8.31
7.51
7.39
7.57
7.39
16.96
17.17
18.28
18.45
17.54
17.71
16.82
17.02
18.98
19.25
19.02
19.25
19.06
19.25
18.96
19.25
247-248
125-126
147-148
137-138
107-108
128-129
190-191
177-178
101-102
103-104
87
76
72
70
69
71
74
73
70
67
6a
6b
6c
6d
6e
6f
6g
6h
6i
69.82
69.61
70.52
70.24
8.31
8.09
7.43
7.25
18.46
18.73
18.78
18.90
641

4-Amino-substituted pyrido[3,4-d]pyrimidine derivatives are generally synthesized in two stages,
initially by chlorination of 3H-pyrido[3,4-d]pyrimidin-4-ones using SOCl2 or POCl3 and then exchange of the
chlorine atom in the intermediate 4-chloropyrido[3,4-d]pyrimidines for an amino group [3]. Another possible
method for the synthesis of the 4-aminopyrido[3,4-d]pyrimidines might be the reaction of 3H-pyrido-
[3,4-d]pyrimidin-4-ones with trifluoromethanesulfonic anhydride and then with amines [11]. Reaction of
compound 3 with trifluoromethanesulfonic anhydride was carried out in methylene chloride at -40ºC and gave
the triflate derivative 4 in 90% yield. This compound reacted with the amines 5a-i upon refluxing in dioxane to
give compounds 6a-i in 67-76% yield.
+
.
NR1R2
N
– R1R2NCN
Ph
N
N
O
N
+
M
6a–i
O
O
N
N
Ph
N
N
N
Ф–187
N
Ф1
1
The composition and structure of compounds 6a-i were confirmed by elemental analysis, IR and H
NMR spectroscopy, and mass spectrometry (Tables 1-3). Interesting information about the properties of
compounds 6a-i can be deduced from the mass spectrometric data.
The presence in the mass spectra of strong peaks for the molecular ions (Irel 100 %) together with the
small number of lower intensity peaks (< 20%) for the fragment ions point to a marked stability of compounds
6a-i towards electron impact (Table 2). One of the most intense peaks in the mass spectra of all of the
TABLE 2. IR and Mass Spectra of Compounds 3 and 6a-i
Com-
pound
IR spectrum (KBr), ν, cm-1
Mass spectrum, m/z (Irel, %)
3
3380 (NH), 1725 (C=O), 1610, 1585, 1574,
1545 (C=N, C=C)
326 [M]+ (100), 236 (18), 187 (40),
163 (30)
6a
1590, 1575, 1535 (C=N, C=C)
379 [M]+ (100), 282 (5), 236 (7), 213 (5),
187 (7)
6b
6c
6d
6e
6f
1590, 1575, 1535 (C=N, C=C)
1588, 1573, 1540 (C=N, C=C)
1585, 1570, 1535 (C=N, C=C)
1585, 1572, 1535 (C=N, C=C)
395 [M]+ (100), 277 (14), 187 (5)
411 [M]+ (100), 187 (10)
436 [M]+ (100), 187 (12), 163 (5)
436 [M]+ (100), 187 (15), 163 (17)
436 [M]+ (100), 187 (5)
3350, 3180 (NH), 1725 (C=O), 1645,
1620 (NH), 1585, 1570, 1530 (C=N, C=C)
6g
3345, 3175 (NH), 1730 (C=O), 1640,
436 [M]+ (100), 187 (17), 163 (8)
1615 (NH), 1585, 1570, 1530 (C=N, C=C)
6h
6i
1585, 1570, 1535 (C=N, C=C)
448 [M]+ (100), 256 (7), 187 (7), 163 (8)
444 [M]+ (100), 187 (8), 176 (12), 106 (8)
1590, 1585, 1570, 1540, 1530 (C=N, C=C)
642

643

compounds 6a-i is the ion peak at mass 187 which suggests a unified decomposition scheme for the given
compounds, the product being the ion not containing the NR1R2 fragment. Analysis of the mass spectra shows
(Table 2) that the first stage of the fragmentation process of compounds 6a-i involves elimination of the
fragments R1R2N–CN from the molecular ions with formation of the ions Φ1 which then undergo elimination of
the benzyl substituent and dehydrogenation to form the relatively stable Φ-187 ions.
The elimination of the R1R2N–CN fragments from the molecular ions was confirmed by PM3
semiempirical calculations for the given compounds and also for their radical cations. Hence, for example, the
calculations showed that the neutral molecule of compound 6a has a marked lengthening of the C(4)–C(4a) bond
and an anomalously large N–C(4)–C(4a) valence angle as a result of repulsion of the pyrrolidine substituent by the
hydrogen atoms of the piperidine ring.
These effects are even more clearly seen in the radical cation RC-6a in which the C(4)–C(4a) and C(2)–N(3)
bonds are lengthened by 0.0220 and 0.0011 Å respectively and the N(1)–C(8a) bond shortened by 0.0341 Å when
compared with the analogous bonds in the neutral molecule 6a (Table 4). The distortion of the N–C(4)–C(4a)
valence angles and strong lengthening of the C(4)–C(4a} bond in the molecules 6a and radical cation RC-6a points
to a marked strain energy, lowering of which is achieved via the elimination of the R1R2N–CN fragment. The
lengthening of the C(4)–C(4a) and C(2)–N(3) bonds in the series of molecules 6a and RC-6a governs only the initial
stage of the process which is completed by full dissociation of the given bonds.
N
4
4a
8a
3
N
N
2
N
N
1
O
6a, RC-6a
The synthesized pyridopyrimidines 3 and 6a-i are white, crystalline compounds which are poorly soluble
in water and in nonpolar organic solvents. The higher melting point of compounds 6f,g is due to the presence in
the molecules of carboxamide groups capable of forming hydrogen bonds.
This study has shown that condensation of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate with
morpholine-4-carboxamidine and subsequent reaction of the 7-benzyl-2-morpholin-4-yl-5,6,7,8-tetrahydro-
3H-pyrido[3,4-d]pyrimidin-4-one with trifluoromethanesulfonic anhydride and amines gives high yields of a
range of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine derivatives.
TABLE 4. Individual PM3 Calculated Valence Angles (ω) and Bond
Lengths (l) in the Pyridopyrimidine Molecule 6a and its Radical Cation
RC-6a
ω, deg
l, Å
Angle
Bond
6a
RC-6a
6a
RC-6a
C(4a)–C(4)–N
N(3)–C(4)–N
127.7
111.8
127.9
111.1
N(1)–C(8a)
C(2)–N(3)
C(4)–C(4a)
1.3651
1.3677
1.4223
1.3310
1.3688
1.4443
644

EXPERIMENTAL
1
IR spectra were taken on a Specord M-80 and H NMR spectra on a Bruker AMX-400 instrument (400
MHz) using TMS as internal standard. Mass spectra were recorded on a Finnigan MAT-90 instrument with an
ionization energy of 70 eV. Column chromatography was carried out on L40/100 grade silica gel. Monitoring of
the reactions was performed by TLC on Silufol UV-254 plates.
The geometry of the molecule of the pyridopyrimidine 6a and its radical cation RC-6a were calculated
out using the PM3 semiempirical method occurring in the HyperChem program package [12]. All of the
calculations were performed with full optimization of the geometric parameters.
Keto ester 1 used in this work came from the company Acros. The method of preparing compound 2 has
been reported in [13].
7-Benzyl-2-morpholin-4-yl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one (3). Compound 2
hydrochloride (24.8 g, 0.15 mol) portionwise and then the keto ester 1 (35.5 g, 0.148 mol) dropwise were added
to a stirred solution of NaOEt prepared from Na (3.5 g, 0.15 mol) and absolute ethanol (200 ml). The reaction
mixture was refluxed for 3 h and ethanol (100 ml) was then distilled off in vacuo. Ammonium chloride was
added to the remaining solution to saturation and the precipitate was filtered off, washed with water, dried in air,
and recrystallized from ethyl acetate.
4-Amino-7-benzyl-2-morpholin-4-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidines (6a-i) (General
Method). Trifluoromethanesulfonic anhydride (3.28 g, 12 mmol) was added dropwise to a stirred suspension of
compound 3 (2.36 g, 10 mmol) and K2CO3 (4 g, 30 mmol) in dry methylene chloride (150 ml) cooled to -40ºC.
The reaction mixture was slowly raised to room temperature, stirred at this temperature for 2 h, and poured into
water (200 ml). The organic layer was separated, dried over Na2SO4, and chromatographed on a short silica gel
column. Solvent was distilled off in vacuo and the residue was dissolved in dry dioxane (150 ml). K2CO3 (4 g,
30 mmol) and the corresponding amine (15 mmol) were added to the solution which was then refluxed for 2 h.
The product was cooled, poured into water (300 ml), extracted with ethyl acetate, and the extract was dried over
Na2SO4 and chromatographed on a short silica gel column. Solvent was removed in vacuo and the residue was
dried and recrystallized from ethyl acetate.
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