Synthesis of 7-arylmethyl-substituted derivatives of 2-amino-2-pyrrolydin- 1-yl-5,6,7,8-tetrahydropyrido-[3,4-d]pyrimidine

Article abstract of DOI:10.1007/s10593-007-0179-6

7-Benzyl-2-pyrrolidin-1-yl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d] pyrimidin-4-one was prepared by condensation of 1-benzyl-4-ethoxycarbonyl-3- oxopiperidine with pyrrolidine-1-carboxamidine. Subsequent treatment of the product with trifluoromethansulfonyl an

Full text of DOI:10.1007/s10593-007-0179-6

Chemistry of Heterocyclic Compounds, Vol. 43, No. 9, 2007
SYNTHESIS OF 7-ARYLMETHYL-
SUBSTITUTED DERIVATIVES OF
2-AMINO-2-PYRROLYDIN-1-YL-
5,6,7,8-TETRAHYDROPYRIDO-
[3,4-d]PYRIMIDINE
A. Yu. Kuznetsov and S. V. Chapyshev
7-Benzyl-2-pyrrolidin-1-yl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one was prepared by
condensation of 1-benzyl-4-ethoxycarbonyl-3-oxopiperidine with pyrrolidine-1-carboxamidine.
Subsequent treatment of the product with trifluoromethansulfonyl anhydride, aqueous ammonia, and
hydrogen in the presence of palladium on carbon gave 4-amino-2-pyrrolidin-1-yl-5,6,7,8-
tetrahydropyrido[3,4-d]pyrimidine in 80% yield. The given compound was used in the reductive
amination of aldehydes in the synthesis of various 7-arylmethyl-substituted derivatives of 4-amino-
2-pyrrolidin-1-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine.
Keywords: 1-benzyl-4-ethoxycarbonyl-3-oxopiperidine, pyrido[3,4-d]pyrimidines, pyrrolidine-1-carbox-
amidine, sodium triacetoxyborohydride, reductive amination, condensation.
Amino-substituted derivatives of pyrido[d]pyrimidines have high biological activity, in particular they
inhibit dehydrofolatereductase, leading to the death of many pathogenic microorganisms [1, 2]. Various structural
analogs of methotrexate (1), for example pyrido[d]pyrimidines 2 and 3 (piritrexim), are among such compounds
with especially high reactivity [3, 4].
O
CO2H
NH2
CO2H
N
H
N
N
N
N
Me
H2N
N
1
NH2
N
Br
NH2 Me
OMe
OMe
OMe
OMe
N
N
N
H2N
H2N
N
N
OMe
OMe
2
3
__________________________________________________________________________________________
Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka 142432,
Moscow Region; e-mail: chap@icp.ac.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9,
1374-1381, September, 2007. Original article submitted June 6, 2006.
0009-3122/07/4309-1167©2007 Springer Science+Business Media, Inc.
1167

In previous work we showed that a suitable method for the synthesis of derivatives of pyrido-
[3,4-d]pyrimidine is the condensation of 1-benzyl-4-ethoxycarbonyl-3-oxopiperidine (4) with morpholine-
4-carboxamidine, which gave 7-benzyl-2-morpholin-4-yl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one [5]
in high yield. In the present work we have studied the condensation of the keto ester 4 with pyrrolidine-
1-carboxamidine (5) and developed a method for the preparation of pyrido[3,,4-d]pyrimidines 10a-d, which are
structural analogs of compounds 2 and 3.
O
N
O
O
H2N
NH
OEt
NaOEt
EtOH
N
+
Ph
N
Ph
N
HN
N
HCl
4
6
5
(F3CSO2)2O
OSO2CF3
N
NH2
N
NH3
Ph
N
Ph
N
N
N
N
N
7
8
H2/Pd–C
NH2
NH2
RCHO
NaHB(OAc)3
N
N
R
N
HN
N
N
N
N
10a–r
9
10 a R = 4-EtC6H4, b R = 4-MeOC6H4, c R = 4-EtOC6H4, d R = 2-FC6H4, e R = 2-HOC6H4,
f R = 2-MeOC6H4, g R = 2-EtOC6H4, h R = 2,4-(MeO)2C6H3, i R = 2-OH-4-MeOC6H3,
j R = 3,4-(MeO)2C6H3, k R = 3-MeO-4-HOC6H3, l R = 3-OH-4-MeOC6H3,
m R = 3-MeO-4-EtOC6H3, n R = 3-HOCH2-4-MeOC6H3, o R = 3-EtO-4-HOC6H3,
p R = 3,5-(MeO)2C6H3, q R = 2,4,5-(MeO)3C6H2, r R = 2-thienyl
Boiling an alcoholic solution of the keto ester 4 with an equimolar amount of amidine 5 in the presence of
1
three equivalents of EtONa for 3 h led to a new compound. According to elemental analysis, IR and H NMR
spectroscopy and mass spectrometry (Tables 1-4), the new compound is 7-benzyl-2-pyrrolidin-1-yl-5,6,7,8-
tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one (6), the yield of which was 73%.
Reaction of compound 6 with trifluoromethanesulfonic anhydride in pyridine at -20°C gave the triflate
derivative 7 in 55% yield. Prolonged heating (12 h, 100°C) of the triflate 7 in a mixture of DMF and aqueous
ammonia gave the amine 8 in 67% yield. Hydrogenation of the amine 8 in methanol solution in the presence of a
suspension of palladium on carbon removed the benzyl substituent and gave the diamine 9 in 80% yield. The
latter readily underwent reductive amination with aldehydes in the presence of sodium triacetoxyborohydride to
give compounds 10a-r with yields of 71-79%.
1168

Table 1. Characteristics of Compounds 6, 8, 9 and 10a-r
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
С
H
N
6
C18H22N4O
69.91
69.65
70.05
69.87
60.46
60.25
71.34
71.18
67.48
67.23
68.21
67.96
66.28
66.03
66.71
66.44
67.48
67.23
68.18
67.96
65.26
65.02
64.46
64.20
65.27
65.02
64.36
64.20
64.47
64.20
65.94
65.77
7.29
7.14
7.37
7.49
7.68
7.77
8.14
8.06
7.64
7.42
7.91
7.70
6.82
6.77
7.22
7.12
7.56
7.42
7.82
7.70
7.48
7.36
7.30
7.09
7.51
7.36
7.32
7.09
7.30
7.09
7.83
7.62
17.79
18.05
22.58
22.63
31.86
31.93
20.52
20.75
20.41
20.63
19.59
19.81
21.04
21.39
21.25
21.52
20.48
20.63
19.62
19.81
18.86
19.03
19.54
19.70
18.86
19.03
19.48
19.70
19.45
18.70
17.96
18.26
228-230
164-165
148-150
175-176
198-200
147-148
190-191
165-166
157-158
155-156
153-154
199-200
163-164
189-190
192-193
159-160
116-117
205-207
140-141
170-171
168-169
73
67
80
78
75
71
74
73
76
72
78
76
79
73
75
74
77
75
76
78
71
8
C18H23N5
9
C11H17N5
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
10r
C20H27N5
C19H25N5O
C20H27N5O
C18H22FN5
C18H23N5O
C19H25N5O
C20H27N5O
C20H27N5O2
C19H25N5O2
C20H27N5O2
C19H25N5O2
C19H25N5O2
C21H29N5O2
C20H27N5O2
C20H27N5O2
C20H27N5O2
C21H29N5O3
C16H21N5S
65.28
65.02
65.24
65.02
65.30
65.02
63.38
63.14
7.52
7.36
7.58
7.36
7.54
7.36
7.48
7.32
18.78
19.03
18.81
19.03
18.78
19.03
17.26
17.53
61.18
60.92
6.92
6.71
21.96
22.20
Signals of the amino group at 5.90 ppm and methylene protons of the piperidine and pyrrolidine rings at
1
1
1.8, 2.5, 2.6, 3.4, and 3.7 ppm are common to the H NMR spectra of compounds 8 and 10a-r. The H NMR
spectra of compounds 6, 8, and 10a-r contain common signals of the methylene protons of the 7-arylmethyl
substituents at 3.2 ppm (Table 5).
Mass spectrometric data provide interesting information on the properties of compounds 6, 8, 9, and
10a-r. Intense peaks of the molecular ions (100%) on a background of a small number of fragment ions shows
that compounds 6, 8, and 10a-r have high stability in an electron impact (Table 3). The presence in the mass
spectra of compounds 6, 8, and 10a-r of peaks of ions with masses 212, 191, 162 indicates a common
fragmentation scheme for these compounds, including the initial loss of the 7-arylmethyl substituent of the
1169

Table 2. IR Spectra of Compounds 6, 8, 9, and 10a-r
Com-
pound
ν, cm-1
ОН
NH
CH
C=C, C=N
6
3230
3010, 2960, 2850
3010, 2960, 2850
3005, 2965, 2850
3010, 2965, 2850
3010, 2960, 2850
3010, 2960, 2850
3010, 2960, 2850
3010, 2960, 2850
3010, 2960, 2850
3010, 2960, 2850
3010, 2960, 2850
3010, 2960, 2850
3010, 2960, 2850
3010, 2960, 2850
3010, 2960, 2850
3010, 2960, 2850
3010, 2960, 2850
3010, 2960, 2850
3010, 2960, 2850
3010, 2960, 2850
3005, 2965, 2850
1610, 1580, 1575, 1545
1590, 1575, 1540
8
3350, 3220, 1675
3350, 3240, 3230, 1675
3355, 3220, 1670
3355, 3220, 1675
3355, 3220, 1675
3355, 3220, 1675
3350, 3220, 1670
3350, 3220, 1675
3350, 3220, 1675
3350, 3220, 1675
3350, 3220, 1675
3350, 3220, 1675
3350, 3220, 1670
3350, 3220, 1675
3350, 3220, 1675
3350, 3220, 1675
3350, 3220, 1675
3350, 3220, 1675
3350, 3220, 1675
3350, 3220, 1675
9
1595, 1580, 1545
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
10r
1585, 1570, 1540
1600, 1585, 1560, 1540
1600, 1580, 1560, 1540
1600, 1585, 1560, 1540
1600, 1580, 1560, 1540
1600, 1585, 1560, 1540
1600, 1585, 1560, 1540
1600, 1585, 1560, 1540
1600, 1580, 1555, 1540
1600, 1585, 1560, 1540
1590, 1565, 1545
3470
3470
3485
3470
1600, 1585, 1560, 1540
1600, 1585, 1560, 1540
1600, 1585, 1560, 1540
1590, 1565, 1545
3495
3485
1600, 1585, 1560, 1540
1600, 1585, 1560, 1540
1590, 1580, 1560, 1540
various derivatives of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine with subsequent decomposition of the piperidine
ring. The fragmentation scheme differs principally from that of the decomposition of 7-benzyl-5,6,7,8-tetrahydro-
pyrido[3,4-d]pyrimidines, with a bulky substituent at position 4, which we studied previously [5]. As a rule, the
.
+
NH2
N
NH2
N
+e
Ph
N
–2e
Ph
N
N
+
N
N
N
.
M
8
(100%)
NH2
NH2
N
– CH2NH
HN
N
+
Ф-162
HN
N
N
N
N
(10–15%)
Ф-191
Ф-212
(10–20%)
(25–65%)
1170

basic direction of fragmentation of the latter included primary decomposition of the pyrimidine ring with
elimination of R–CN units. Apparently the strong electron-donor pyrrolidine substituent in position 2 of
compounds 6, 8, and 10a-r strongly increases the binding electron density in their pyrimidine rings, directing
fragmentation into the primary decomposition of the piperidine ring.
This work shows that condensation of 1-benzyl-4-ethoxycarbonyl-3-oxopiperidine with pyrrolidine-
1-carboxamidine permits the preparation in high yield of 7-benzyl-2-pyrrolidin-4-yl-5,6,7,8-tetrahydro-
3H-pyrido[3,4-d]pyrimidin-4-one, which may be used as the key starting material in the synthesis of a variety of
derivatives of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine.
Table 3. Mass Spectra of Compounds 6, 8, 9, and 10a-r
Com-
pound
m/z (Irel, %)
6
310 [M]+ (100), 192 (30)
8
9
309 [M]+ (100), 212 (25), 191 (10), 162 (10)
219 [M]+ (25), 191 (15), 156 (100), 79 (50)
337 [M]+ (100), 212 (35), 162 (10), 83 (25)
339 [M]+ (100), 212 (55), 162 (5)
353 [M]+ (100), 212 (35), 151 (5), 107 (5)
327 [M]+ (100), 212 (40), 191 (30), 162 (15)
325 [M]+ (100), 212 (65), 191 (15), 162 (5), 107 (5)
339 [M]+ (100), 212 (30), 191 (15)
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
10r
353 [M]+ (100), 212 (40), 191 (15), 162 (5)
369 [M]+ (100), 212 (25), 167 (20), 151 (15), 137 (5)
355 [M]+ (50), 221 (65), 212 (100), 191 (20), 162 (15), 151 (5), 137 (25)
369 [M]+ (100), 212 (20), 191 (5), 162 (5), 151 (5)
355 [M]+ (100), 212 (35), 162 (5), 137 (20)
355 [M]+ (100), 212 (35), 162 (5)
383 [M]+ (100), 212 (15), 181 (5), 137 (5), 79 (5)
369 [M]+ (100), 212 (20), 167 (10)
369 [M]+ (100), 212 (15), 151 (10), 79 (5)
369 [M]+ (100), 212 (20), 151 (10)
399 [M]+ (100), 212 (20), 198 (5), 181 (20), 167 (40)
316 [M]+ (100), 212 (55), 191 (15), 162 (5)
Table 4. 1H NMR Spectra of Compounds 6, 8-10
Chemical shifts, δ, ppm
Com-
2-N(CH2)4,
4H, br. s
pound
5-CH2
6-CH2
8-CH2
Ar–CH2*
NH2
NH
6
2.45
2.45
2.30
2.45
2.60
2.60
2.60
2.60
3.65
3.65
3.65
3.65
3.20
3.20
1.83, 3.38
1.83, 3.38
1.83, 3.38
1.83, 3.38
10.2
5.6
8
5.90
6.10
5.90
9
10
3.20
_______
* See Table 5.
1171

Table 5. 1H NMR Spectra of Compounds 6, 8-10 (Signals of the Protons of
the Ar Fragment)
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
6
7.25 (3H, m, H-3',4',5'); 7.32 (2H, d, J = 8.5, H-2',6')
7.25 (3H, m, H-3',4',5'); 7.32 (2H, d, J = 8.5, H-2',6')
8
10a
1.10 (3H, t, J = 6.5, CH3); 2.60 (2H, m, CH2); 7.17 (2H, d, J = 8.5, H-3',5');
7.26 (2H, d, J = 8.5, H-2',6')
10b
10c
3.75 (3H, s, OCH3); 6.88 (2H, d, J = 8.5, H-3',5'); 7.26 (2H, d, J = 8.5, H-2',6')
1.35 (3H, t, J = 6.5, CH3); 4.00 (2H, q, J = 6.5, OCH2); 6.87 (2H, d, J = 8.5, H-3',5');
7.24 (2H, d, J = 8.5, H-2',6')
10d
10e
10f
7.15 (2H, m, H-6',4'); 7.30 (1H, dd, JН-Н = 8.5, JF-H = 6.0, H-3'); 7.46 (1H, t, J = 8.5, H-5')
6.76 (2H, m, H-3',5'); 7.13 (2H, m, H-4',6'); 10.0 (1H, br. s, OH)
3.80 (3H, s, OCH3); 6.91 (1H, t, J = 8.5, H-5'); 6.97 (1H, d, J = 8.5, H-3');
7.22 (1H, t, J = 8.5, H-4'); 7.35 (1H, d, J = 8.5, H-6')
10g
10h
10i
1.34 (3H, t, J = 6.5, CH3); 4.05 (2H, q, J = 6.5, OCH2); 6.90 (1H, t, J = 8.5, H-5');
6.95 (1H, d, J = 8.5, H-3'); 7.19 (1H, t, J = 8.5, H-4'); 7.35 (1H, d, J = 8.5, H-6')
3.75 (3H, s, OCH3); 3.80 (3H, s, OCH3); 6.50 (1H, dd, J = 8.5, J = 1.5, H-5');
6.57 (1H, d, J = 1.5, H-3'); 7.25 (1H, d, J = 8.5, H-6')
3.70 (3H, s, OCH3); 6.33 (2H, m, H-3',5'); 7.00 (1H, d, J = 8.5, H-6');
10.0 (1H, br. s, OH)
10j
10k
10l
3.75 (6H, s, 2OCH3); 6.33 (3H, m, H-2',5',6')
3.80 (3H, s, OCH3); 6.80 (2H, s, H-5',6'); 6.90 (1H, s, H-2'); 8.70 (1H, s, OH)
3.75 (3H, s, OCH3); 6.71 (1H, d, J = 8.5, H-6'); 6.80 (1H, s, H-2');
6.85 (1H, d, J = 8.5, H-5'); 8.70 (1H, s, OH)
10m
10n
10o
1.30 (3H, t, J = 6.5, CH3); 3.75 (3H, s, OCH3); 4.00 (2H, q, J = 6.5, OCH2);
6.84 (1H, d, J = 8.5 , H-5'); 6.87 (1H, d, J = 8.5, H-6'); 6.90 (1H, s, H-2')
3.75 (3H, s, OCH3); 4.50 (2H, d, J = 5.5, CH2); 4.85 (1H, t, J = 5.5, ОН);
6.80 (1H, d, J = 8.5, H-5'); 7.18 (1H, d, J = 8.5, H-6'); 7.38 (1H, s, H-2')
1.30 (3H, t, J = 6.5, CH3); 4.00 (2H, q, J = 6.5, OCH2); 6.71 (2H, s, H-5',6');
6.89 (1H, s, H-2'); 8.55 (1H, s, OH)
10p
10q
3.75 (6H, s, 2OCH3); 6.38 (1H, s, H-4'); 6.54 (2H, s, H-2',6')
3.75 (3H, s, OCH3); 3.80 (3H, s, OCH3); 3.85 (3H, s, OCH3); 6.68 (1H, s, H-3');
6.96 (1H, s, H-6')
10r
6.98 (1H, dd, J = 5.4, J = 4.0, H-4'); 7.03 (1H, d, J = 4.0, H-3'); 7.41 (1H, d, J = 5.5, H-5')
EXPERIMENTAL
1
IR spectra of KBr disks were recorded on a Specord M-80 machine, H NMR spectra of DMSO-d6
solutions with TMS as internal standard were recorded with a Bruker AMX-400 machine (400 MHz). Mass
spectra were recorded with a Finnigan MAT-90 machine with an ionization energy of 70 eV. Silicagel, type
L 40/100, was used for column chromatography. Reactions were monitored by TLC on Silufol UV-254 platess.
The keto ester 4 was obtained from the Acros company. The preparation of amidine 5 was described
elsewhere [6].
7-Benzyl-2-pyrrolidin-1-yl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]-pyrimidin-4-one (6). Amidine hydro-
chloride 5 (22.4 g, 150 mmol) was added in small portions to a stirred solution of NaOEt, prepared from Na
(7.0 g, 300 mmol) and absolute ethanol (300 ml). The keto ester 4 (35.5 g, 148 mmol) was then added dropwise,
the mixture was boiled for 3 h, the solvent was removed in vacuum, and the residue was added to saturated
aqueous solution of ammonium chloride. The residue which did not dissolve in water was filtered off, washed
with water, methanol, and then ether, and dried in the air.
1172

4-Amino-7-benzyl-2-pyrrolidin-1-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine [8]. Trifluromethane-
sulfonic anhydride (4.92 g, 12 mmol) was added dropwise to a stirred suspension of compound 6 (5.58 g,
18 mmol) in pyridine (50 ml) cooled to -20°C, after which the reaction temperature was allowed to rise slowly to
room temperature. The mixture was stirred for 20 min at room temperature and poured into water (500 ml). The
precipitate was filtered off, washed with water, and dried in the air. The yield of triflate 7 was 4 g (53%). The
triflate was dissolved in DMF (20 ml), potassium carbonate (6.7 g, 50 mmol) and 25% aqueous ammonia (5 ml)
were added to the solution, which was then stirred at 100°C for 12 h, then cooled and diluted with water (200 ml).
The product was extracted with dichloromethane (2 x 200 ml), the extract was dried over Na2SO4, and the solvent
was removed in vacuum. The residue was recrystallized from ethyl acetate.
4-Amino-2-pyrrolidin-1-yl-5,6,7,8-tetrahydro[3,4-d]pyrimidine (9). A solution of compound 8
(15.45 g, 50 mmol) in methanol (300 ml) was hydrogenated under a pressure of 3 atm at 50°C in the presence of
10% palladium on charcoal (0.7 g). After absorption of the calculated amount of hydrogen (50 mmol), the catalyst
was filtered from the solution which was then reduced to 80% in vacuum. The precipitate was filtered off, washed
with ether and dried in the air.
4-Amino-7-arylmethyl-2-pyrrolidin-1-yl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidines 10a-r. To a
solution of compound 9 in dry dichloromethane (10 ml), an aldehyde (2.6 mmol), triethylamine (1 ml, 8 mmol),
and three drops of acetic acid were added, and the mixture was stirred at room temperature for 3 h. NaHB(OAc)3
(1.25 g, 6 mmol) was added in small portions and the mixture was stirred at room temperature for 48 h. After the
reaction was completed a saturated aqueous solution of Na2CO3 (20 ml) was added. The reaction product was
extracted with dichloromethane (2×20 ml), the extract was washed with a saturated aqueous solution of CaCl2 and
dried over Na2SO4. The solvent was removed in vacuum, and the residue was chromatographed on a column of
silica gel with 1:3 ethyl acetate–hexane as eluent.
The properties of compounds 6, 8, 9, and 10a-r are cited in Tables 1-5.
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